Targeted Protein Degradation: Clinical Advances in the Field of Oncology
Abstract
:1. Introduction
2. Targeted Protein Degradation Approaches
2.1. Hijacking the UPS
2.1.1. PROTACs (PROteolysis TArgeting Chimeras)
2.1.2. Tag-Based Chemical Degraders
2.1.3. Degrader Systems Based on PROTACs
Homo-PROTACs as Suicide Molecules
Nucleic Acid-Based PROTACs
- RNA-PROTACs
- Transcription Factor PROTACs
- G4-PROTACs
- Aptamer-PROTACs
2.1.4. Molecular Glues
2.1.5. SNIPERs
2.2. Hijacking the Non-UPS
2.2.1. (Macro)autophagy Degradation Targeting Chimeras
2.2.2. Harnessing Endolysosomal Pathways
2.2.3. RIBOTACs
3. Clinical Advances of Chemical Degraders in Oncology
3.1. PROTAC-Based Clinical Trials
3.1.1. AR PROTAC
3.1.2. ER PROTAC
3.1.3. BTK PROTAC
3.1.4. BRD4 PROTAC
3.1.5. BRD9 PROTAC
3.1.6. STAT3 PROTAC
3.1.7. BCL-xL PROTAC
3.1.8. Other PROTACs
3.2. Molecular Glue-Based Clinical Trials
4. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
2H2022 | Second half of the year 2022 |
AbTAC | Antibody-based PROTAC |
AD | Atopic dermatitis |
ADMET | Absorption, distribution, metabolism, excretion and toxicity |
AGA | Androgenetic alopecia |
AhR | Aryl hydrocarbon receptor |
AID | Auxin-inducible degron |
ALK | Anaplastic lymphoma kinase |
AML | Acute myeloid leukemia |
AR | Androgen receptor |
ASGPR | Asialoglycoprotein receptor |
ASO | Antisense oligonucleotide |
aTAG ATP | AchillesTag Adenosine triphosphate |
ATTEC | Autophagy tethering compound |
AUTAC | Autophagy targeting chimera |
AUTOTAC | Autophagy targeting chimera |
Bcl | B-cell lymphoma |
BCL-xL | B-cell lymphoma-extra large |
BCR | Breakpoint cluster region protein |
BET | Bromo- and extra-terminal family |
BIAC | Bispecific aptamer chimera |
BRAF | V-raf murine sarcoma viral oncogene homolog B1 |
BRD | Bromodomain-containing protein |
BTK | Bruton’s tyrosine kinase |
CAR | Chimeric antigen receptor |
CDC20 | Cell division cycle 20 |
CDK | Cyclin-dependent kinase |
Cer | Ceritinib |
cIAP | Cellular inhibitor of apoptosis |
CI-M6PR | Cation-independent mannose-6-phosphonate receptor |
CK1α | Casein kinase 1α |
CK2 | Casein kinase 2 |
CLIPTAC | In-cell-click-formed proteolysis targeting chimera |
CLL | Chronic lymphocytic leukemia |
CMA | Chaperone-mediated autophagy |
CPP-LSS | Cell-penetrating peptide and lysosome-sorting sequence |
CRABP I/II | Cellular retinoic acid-binding protein 1/2 |
CRBN | Cereblon |
CREPT | Cell cycle-related and expression elevated protein in tumor |
CRISPR | Clustered regularly interspaced short palindromic repeats |
CT | Computed tomography |
CYP1B1 DCAF5 | Cytochrome p450 family 1 subfamily B member 1 DDB1 and CUL4 associated factor 5 |
DCAF | DDB1 and CUL4 associated factor |
DHODH | Dihydroorotate dehydrogenase |
DHX36 | DEAH-box-protein 36 |
DLBCL DNA | Diffuse large B cell lymphoma Deoxyribonucleid acid |
dsDNA | Double-stranded DNA |
dTAG | Degrader tag |
DUB | Deubiquitinating enzyme |
DUBTAC | Deubiquitinase-targeting chimera |
eEF2K | Eukaryotic elongation factor 2 kinase |
EGFR | Epidermal growth factor receptor |
eIF4E | Eukaryotic initiating factor 4E |
EML4 | Echinoderm microtubule-associated protein-like 4 |
ER | Estrogen receptor |
ErbB3 | Erb-b2 receptor tyrosine kinase 3 |
ERK | Extracellular signal-regulated kinase |
ESR1 | Estrogen receptor 1 |
EZH2 | Enhancer of zeste homolog 2 |
FAK | Focal adhesion kinase |
FDA | Food and drug administration |
FEM1B | Feminization-1 homolog b |
FKBP | FK506-binding proteins |
FLT3 | Fms-like tyrosine kinase 3 |
FOXO1 GlueTAC | Forkhead box protein O1 GlueBody Chimera |
GNPs | Gold nanoparticles |
GPD1L | Glycerol-3-phosphate dehydrogenase 1 like protein |
GREB1 | Growth regulating estrogen receptor binding 1 |
GSTP1 G4 | G1 to S phase transition 1 G-quadruplex |
HDAC | Histone deacetylase |
HECT | Homology to E6AP C terminus |
HER | Human epidermal growth factor receptor |
HIF-1-alpha | Hypoxia-inducible factor 1-alpha |
HIP1R | Huntingtin-interacting protein 1–related |
HPK1 | Hematopoietic progenitor kinase 1 |
HS HyT IAP | Hidradenitis suppurativa Hydrophobic tagging Inhibitors of apoptosis protein |
IDO1 | Indoleamine 2,3-dioxygenase 1 |
IGF-1R | Insulin-like growth factor 1 receptor |
IKZF | IKAROS zinc finger family |
IMiD | Immunomodulatory drug |
IND | Investigational new drug |
IRAK4 | Interleukin-1 receptor-associated kinase 4 |
ITK IV | Interleukin-2-inducible T-cell kinase Intravenous injection |
JAK | Janus kinase |
JAMM | Jab1/MPN domain-associated metallopeptidase |
KEAP1 | Kelch-like ECH associated protein 1 |
LC3 | Microtubule-associated protein 1A/1B-light chain 3 |
LD | Lipid droplets |
LEF1 | Lymphoid enhancer binding factor 1 |
LGL | Large granular lymphocyte |
LHRH | Luteinizing hormone-releasing hormone |
LIR | LC3-interacting region |
LTR | Lysosomal targeted receptor |
LYTAC | Lysosome targeting chimera |
MCL | Mantle cell lymphoma |
Mcl-1 | Myeloid cell leukemia-1 |
MCPIP | Monocyte chemotactic protein-induced protein |
mCRPC | Metastatic castration-resistant prostate cancer |
MDM2 | Mouse double minute 2 |
MEK | Mitogen-activated protein kinase kinase |
Met | Mesenchymal epithelial transition |
mHTT | Mutant huntingtin |
MINDY | Motif interacting with Ub-containing novel DUB family |
miR-96 | MicroRNA 96 |
MJD | Machado–Joseph disease protein domain |
MM | Multiple myeloma |
MoDE-A | Molecular degrader of extracellular proteins through the ASGPR |
MRI | Magnetic resonance imaging |
MTH1 | MutT homolog-1 |
MyD88 | Myeloid differentiation primary response 88 |
NF-κB | Nuclear factor kappa-light-chain-enhancer of activated B cells |
NHL | Non-Hodgkin’s lymphoma |
NRAS | Neuroblastoma RAS viral oncogene homolog |
NSCLC | Non-small cell lung cancer |
NTRK | Neurotrophic tyrosine receptor kinase |
NVOC | Nitroveratryloxycarbonyl |
OTU | Ovarian tumor protease |
PARP1 | Poly [ADP-ribose] polymerase 1 |
PB1 | Phox and Bem1 domain |
PDE | Phosphodiesterase |
PD-L1 | Programmed death-ligand 1 |
PDX | Patient derived xenograft |
PEG | Polyethylene glycol |
PHOTAC | Photochemically targeting chimera |
PI3K | Phosphoinositide 3-kinases |
PLK1 PO | Polo-like kinase 1 Per os |
POI | Protein of interest |
POLY-PROTAC | Polymeric PROTAC |
Pom | Pomalidomide |
PR | Progesterone receptor |
PRC | Polycomb repressive complex |
PRMT5 | Protein arginine methyltransferase 5 |
PROTACs | Proteolysis targeting chimeras |
PTB | Phosphotyrosine-binding |
PTK-7 | Protein kinase-like 7 |
R/R | Relapsed/refractory |
RAS | Rat sarcoma |
RBFOX1 | RNA binding Fox-1 homolog 1 |
RBM23 | RNA binding motif protein 23 |
RBM39 | RNA binding motif protein 39 |
RBP | RNA binding protein |
RBR | RING-between-RING |
RHAU | RNA helicase associated with AU-rich element |
RIBOTAC | Ribonuclease Targeting chimera |
RING | Really interesting new gene |
RIPK2 RNA | Receptor interacting serine/threonine kinase 2 Ribonucleic acid |
RNF | RING finger protein |
RTK SC | Receptor tyrosine kinase Subcutaneous injection |
SCLC | Small cell lung cancer |
SERD | Selective estrogen receptor degrader |
SGK | Serum/glucocorticoid regulated kinase family member |
SH2 | Src homology 2 |
SHP2 | Src homology 2 domain containing protein tyrosine phosphatase-2 |
siRNA | Small interfering RNA |
SirT2 | Sirtuin 2 |
SLC9A1 | Solute carrier family 9 member A1 |
SLE | Systemic lupus erythematosus |
SLL | Small lymphocytic lymphoma |
SMARCB1 | SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily B, member 1 |
SNIPER | Specific and non-genetic inhibitors of apoptosis protein (IAP)-dependent protein eraser |
SPAAC | Strain-promoted azide–alkyne cycloaddition |
SRC-1 | Steroid receptor coactivator-1 |
STAT3 | Signal transducer and activator of transcription 3 |
TACC3 | Transforming acidic coiled-coil containing protein 3 |
TBK1 | TANK-binding kinase 1 |
TCF | T-cell factor |
TCL | T-cell lymphomas |
TCO | Trans-cyclooctene |
TF | Transcription factor |
TFF | Trefoil factor |
TGF-β1 | Transforming growth factor beta 1 |
TI | Tumor-infiltrating |
TOI | Transcription factor of interest |
TPD | Targeted protein degradation |
TPS | Targeted protein stabilization |
TRAFTAC | Transcription factor targeting Chimera |
Treg | Regulatory T cell |
TRIM24 | Tripartite motif containing 24 |
TrkA | Tropomyosin receptor kinase A |
TZ | Tetrazine |
Ub | Ubiquitin |
UCH | Ubiquitin C-terminal hydrolase |
UPS | Ubiquitin-proteasome system |
USP | Ubiquitin-specific protease |
UV | Ultraviolet |
VEGFR | Vascular endothelial growth factor receptor |
VHL | Von Hippel-Lindau |
WM | Waldenström macroglobulinaemia |
XIAP | X-linked inhibitor of apoptosis protein |
ZUFSP | Zn-finger and UFSP domain protein |
α1A-AR | Alpha-1A adrenergic receptor |
References
- Sung, H.; Ferlay, J.; Siegel, R.L.; Laversanne, M.; Soerjomataram, I.; Jemal, A.; Bray, F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J. Clin. 2021, 71, 209–249. [Google Scholar] [CrossRef]
- Ferlay, J.; Colombet, M.; Soerjomataram, I.; Parkin, D.M.; Piñeros, M.; Znaor, A.; Bray, F. Cancer statistics for the year 2020: An overview. Int. J. Cancer 2021, 149, 778–789. [Google Scholar] [CrossRef] [PubMed]
- Salami, J.; Crews, C.M. Waste disposal-An attractive strategy for cancer therapy. Science 2017, 355, 1163–1167. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Mir, O.; Broutin, S.; Desnoyer, A.; Delahousse, J.; Chaput, N.; Paci, A. Pharmacokinetics/Pharmacodynamic (PK/PD) relationship of therapeutic monoclonal antibodies used in oncology: What’s new? Eur. J. Cancer 2020, 128, 103–106. [Google Scholar] [CrossRef] [PubMed]
- Bedard, P.L.; Hyman, D.M.; Davids, M.S.; Siu, L.L. Small molecules, big impact: 20 years of targeted therapy in oncology. Lancet 2020, 395, 1078–1088. [Google Scholar] [CrossRef]
- Lai, A.C.; Crews, C.M. Induced protein degradation: An emerging drug discovery paradigm. Nat. Rev. Drug Discov. 2017, 16, 101–114. [Google Scholar] [CrossRef] [Green Version]
- Migliorati, J.M.; Liu, S.; Liu, A.; Gogate, A.; Nair, S.; Bahal, R.; Rasmussen, T.P.; Manautou, J.E.; Zhong, X.-B. Absorption, Distribution, Metabolism, and Excretion of US Food and Drug Administration-Approved Antisense Oligonucleotide Drugs. Drug Metab. Dispos. 2022, 50, 888–897. [Google Scholar] [CrossRef]
- Padda, I.S.; Mahtani, A.U.; Parmar, M. Small Interfering RNA (SiRNA) Based Therapy; StatPearls Publishing: Treasure Island, FL, USA, 2022. [Google Scholar]
- Marques, J.T.; Williams, B.R.G. Activation of the mammalian immune system by siRNAs. Nat. Biotechnol. 2005, 23, 1399–1405. [Google Scholar] [CrossRef]
- Dahlman, J.E.; Kauffman, K.J.; Langer, R.; Anderson, D.G. Nanotechnology for in vivo targeted siRNA delivery. Adv. Genet. 2014, 88, 37–69. [Google Scholar] [CrossRef]
- Wilhelm, S.; Tavares, A.J.; Dai, Q.; Ohta, S.; Audet, J.; Dvorak, H.F.; Chan, W.C.W. Analysis of nanoparticle delivery to tumours. Nat. Rev. Mater. 2016, 1, 16014. [Google Scholar] [CrossRef]
- Fedorov, Y.; Anderson, E.M.; Birmingham, A.; Reynolds, A.; Karpilow, J.; Robinson, K.; Leake, D.; Marshall, W.S.; Khvorova, A. Off-target effects by siRNA can induce toxic phenotype. RNA 2006, 12, 1188–1196. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Teicher, B.A.; Tomaszewski, J.E. Proteasome inhibitors. Biochem. Pharmacol. 2015, 96, 1–9. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Vitale, G. Molecular glues begin to stick. C EN Glob. Enterp. 2022, 100, 20–24. [Google Scholar] [CrossRef]
- Donovan, K.A.; An, J.; Nowak, R.P.; Yuan, J.C.; Fink, E.C.; Berry, B.C.; Ebert, B.L.; Fischer, E.S. Thalidomide promotes degradation of SALL4, a transcription factor implicated in Duane Radial Ray syndrome. Elife 2018, 7, e38430. [Google Scholar] [CrossRef] [PubMed]
- Békés, M.; Langley, D.R.; Crews, C.M. PROTAC targeted protein degraders: The past is prologue. Nat. Rev. Drug Discov. 2022, 21, 181–200. [Google Scholar] [CrossRef]
- Yamazoe, S.; Tom, J.; Fu, Y.; Wu, W.; Zeng, L.; Sun, C.; Liu, Q.; Lin, J.; Lin, K.; Fairbrother, W.J.; et al. Heterobifunctional Molecules Induce Dephosphorylation of Kinases-A Proof of Concept Study. J. Med. Chem. 2020, 63, 2807–2813. [Google Scholar] [CrossRef] [PubMed]
- Siriwardena, S.U.; Godage, D.N.P.M.; Shoba, V.M.; Lai, S.; Shi, M.; Wu, P.; Chaudhary, S.K.; Schreiber, S.L.; Choudhary, A. Phosphorylation-Inducing Chimeric Small Molecules. J. Am. Chem. Soc. 2020, 142, 14052–14057. [Google Scholar] [CrossRef]
- Henning, N.J.; Boike, L.; Spradlin, J.N.; Ward, C.C.; Liu, G.; Zhang, E.; Belcher, B.P.; Brittain, S.M.; Hesse, M.J.; Dovala, D.; et al. Deubiquitinase-targeting chimeras for targeted protein stabilization. Nat. Chem. Biol. 2022, 18, 412–421. [Google Scholar] [CrossRef] [PubMed]
- Daniels, D.L.; Winter, G.E. Degrading boundaries to break new ground in chemical biology. Curr. Res. Chem. Biol. 2022, 2, 100033. [Google Scholar] [CrossRef]
- Nam, T.; Han, J.H.; Devkota, S.; Lee, H.-W. Emerging Paradigm of Crosstalk between Autophagy and the Ubiquitin-Proteasome System. Mol. Cells 2017, 40, 897–905. [Google Scholar] [CrossRef] [PubMed]
- Popovic, D.; Vucic, D.; Dikic, I. Ubiquitination in disease pathogenesis and treatment. Nat. Med. 2014, 20, 1242–1253. [Google Scholar] [CrossRef] [PubMed]
- Antao, A.M.; Tyagi, A.; Kim, K.-S.; Ramakrishna, S. Advances in Deubiquitinating Enzyme Inhibition and Applications in Cancer Therapeutics. Cancers 2020, 12, 1579. [Google Scholar] [CrossRef] [PubMed]
- Komander, D.; Rape, M. The Ubiquitin Code. Annu. Rev. Biochem. 2012, 81, 203–229. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Alabi, S.B.; Crews, C.M. Major advances in targeted protein degradation: PROTACs, LYTACs, and MADTACs. J. Biol. Chem. 2021, 296, 100647. [Google Scholar] [CrossRef] [PubMed]
- Costales, M.G.; Aikawa, H.; Li, Y.; Childs-Disney, J.L.; Abegg, D.; Hoch, D.G.; Velagapudi, S.P.; Nakai, Y.; Khan, T.; Wang, K.W.; et al. Small-molecule targeted recruitment of a nuclease to cleave an oncogenic RNA in a mouse model of metastatic cancer. Proc. Natl. Acad. Sci. USA 2020, 117, 2406–2411. [Google Scholar] [CrossRef] [Green Version]
- Sabapathy, K.; Lane, D.P. Therapeutic targeting of p53: All mutants are equal, but some mutants are more equal than others. Nat. Rev. Clin. Oncol. 2018, 15, 13–30. [Google Scholar] [CrossRef]
- Sakamoto, K.M.; Kim, K.B.; Kumagai, A.; Mercurio, F.; Crews, C.M.; Deshaies, R.J. Protacs: Chimeric molecules that target proteins to the Skp1-Cullin-F box complex for ubiquitination and degradation. Proc. Natl. Acad. Sci. USA 2001, 98, 8554–8559. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Sakamoto, K.M.; Kim, K.B.; Verma, R.; Ransick, A.; Stein, B.; Crews, C.M.; Deshaies, R.J. Development of Protacs to target cancer-promoting proteins for ubiquitination and degradation. Mol. Cell. Proteom. 2003, 2, 1350–1358. [Google Scholar] [CrossRef] [Green Version]
- Cyrus, K.; Wehenkel, M.; Choi, E.-Y.; Swanson, H.; Kim, K.-B. Two-headed PROTAC: An effective new tool for targeted protein degradation. Chembiochem 2010, 11, 1531–1534. [Google Scholar] [CrossRef]
- Schneekloth, A.R.; Pucheault, M.; Tae, H.S.; Crews, C.M. Targeted intracellular protein degradation induced by a small molecule: En route to chemical proteomics. Bioorg. Med. Chem. Lett. 2008, 18, 5904–5908. [Google Scholar] [CrossRef] [PubMed]
- Hines, J.; Gough, J.D.; Corson, T.W.; Crews, C.M. Posttranslational protein knockdown coupled to receptor tyrosine kinase activation with phosphoPROTACs. Proc. Natl. Acad. Sci. USA 2013, 110, 8942–8947. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Wang, Z.-W.; Liu, Y.; Zhu, X. PhotoPROTACs: A Novel Biotechnology for Cancer Treatment. Trends Cell Biol. 2020, 30, 749–751. [Google Scholar] [CrossRef] [PubMed]
- Reynders, M.; Matsuura, B.S.; Bérouti, M.; Simoneschi, D.; Marzio, A.; Pagano, M.; Trauner, D. PHOTACs enable optical control of protein degradation. Sci. Adv. 2020, 6, 934–951. [Google Scholar] [CrossRef] [Green Version]
- Pfaff, P.; Samarasinghe, K.T.G.; Crews, C.M.; Carreira, E.M. Reversible Spatiotemporal Control of Induced Protein Degradation by Bistable PhotoPROTACs. ACS Cent. Sci. 2019, 5, 1682–1690. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Liu, J.; Chen, H.; Ma, L.; He, Z.; Wang, D.; Liu, Y.; Lin, Q.; Zhang, T.; Gray, N.; Kaniskan, H.Ü.; et al. Light-induced control of protein destruction by opto-PROTAC. Sci. Adv. 2020, 6, 969–986. [Google Scholar] [CrossRef] [Green Version]
- Graham, H. The mechanism of action and clinical value of PROTACs: A graphical review. Cell. Signal. 2022, 99, 110446. [Google Scholar] [CrossRef] [PubMed]
- Yang, X.; Yin, H.; Kim, R.D.; Fleming, J.B.; Xie, H. Preclinical and Clinical Advances of Targeted Protein Degradation as a Novel Cancer Therapeutic Strategy: An Oncologist Perspective. Target. Oncol. 2021, 16, 1–12. [Google Scholar] [CrossRef] [PubMed]
- Bondeson, D.P.; Smith, B.E.; Burslem, G.M.; Buhimschi, A.D.; Hines, J.; Jaime-Figueroa, S.; Wang, J.; Hamman, B.D.; Ishchenko, A.; Crews, C.M. Lessons in PROTAC design from selective degradation with a promiscuous warhead. Cell Chem. Biol. 2018, 25, 78. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Brand, M.; Jiang, B.; Bauer, S.; Donovan, K.A.; Liang, Y.; Wang, E.S.; Nowak, R.P.; Yuan, J.C.; Zhang, T.; Kwiatkowski, N.; et al. Homolog-Selective Degradation as a Strategy to Probe the Function of CDK6 in AML. Cell Chem. Biol. 2019, 26, 300–306.e9. [Google Scholar] [CrossRef]
- Tovell, H.; Testa, A.; Zhou, H.; Shpiro, N.; Crafter, C.; Ciulli, A.; Alessi, D.R. Design and Characterization of SGK3-PROTAC1, an Isoform Specific SGK3 Kinase PROTAC Degrader. ACS Chem. Biol. 2019, 14, 2024–2034. [Google Scholar] [CrossRef]
- Potjewyd, F.; Turner, A.-M.W.; Beri, J.; Rectenwald, J.M.; Norris-Drouin, J.L.; Cholensky, S.H.; Margolis, D.M.; Pearce, K.H.; Herring, L.E.; James, L.I. Degradation of Polycomb Repressive Complex 2 with an EED-Targeted Bivalent Chemical Degrader. Cell Chem. Biol. 2020, 27, 47–56.e15. [Google Scholar] [CrossRef]
- Farnaby, W.; Koegl, M.; Roy, M.J.; Whitworth, C.; Diers, E.; Trainor, N.; Zollman, D.; Steurer, S.; Karolyi-Oezguer, J.; Riedmueller, C.; et al. BAF complex vulnerabilities in cancer demonstrated via structure-based PROTAC design. Nat. Chem. Biol. 2019, 15, 672–680. [Google Scholar] [CrossRef] [PubMed]
- Chen, H.; Chen, F.; Pei, S.; Gou, S. Pomalidomide hybrids act as proteolysis targeting chimeras: Synthesis, anticancer activity and B-Raf degradation. Bioorg. Chem. 2019, 87, 191–199. [Google Scholar] [CrossRef]
- Jiang, B.; Gao, Y.; Che, J.; Lu, W.; Kaltheuner, I.H.; Dries, R.; Kalocsay, M.; Berberich, M.J.; Jiang, J.; You, I.; et al. Discovery and resistance mechanism of a selective CDK12 degrader. Nat. Chem. Biol. 2021, 17, 675–683. [Google Scholar] [CrossRef] [PubMed]
- Gosavi, P.M.; Ngan, K.C.; Yeo, M.J.R.; Su, C.; Li, J.; Lue, N.Z.; Hoenig, S.M.; Liau, B.B. Profiling the Landscape of Drug Resistance Mutations in Neosubstrates to Molecular Glue Degraders. ACS Cent. Sci. 2022, 8, 417–429. [Google Scholar] [CrossRef] [PubMed]
- Hanzl, A.; Barone, E.; Bauer, S.; Yue, H.; Nowak, R.P.; Hahn, E.; Pankevich, E.V.; Koren, A.; Kubicek, S.; Fischer, E.S.; et al. E3-specific degrader discovery by dynamic tracing of substrate receptor abundance. bioRxiv 2022. [Google Scholar] [CrossRef]
- Zhang, L.; Riley-Gillis, B.; Vijay, P.; Shen, Y. Acquired Resistance to BET-PROTACs (Proteolysis-Targeting Chimeras) Caused by Genomic Alterations in Core Components of E3 Ligase Complexes. Mol. Cancer Ther. 2019, 18, 1302–1311. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- He, M.; Cao, C.; Ni, Z.; Liu, Y.; Song, P.; Hao, S.; He, Y.; Sun, X.; Rao, Y. PROTACs: Great opportunities for academia and industry (an update from 2020 to 2021). Signal Transduct. Target. Ther. 2022, 7, 181. [Google Scholar] [CrossRef] [PubMed]
- Khan, S.; He, Y.; Zhang, X.; Yuan, Y.; Pu, S.; Kong, Q.; Zheng, G.; Zhou, D. PROteolysis TArgeting Chimeras (PROTACs) as emerging anticancer therapeutics. Oncogene 2020, 39, 4909–4924. [Google Scholar] [CrossRef]
- Li, X.; Pu, W.; Zheng, Q.; Ai, M.; Chen, S.; Peng, Y. Proteolysis-targeting chimeras (PROTACs) in cancer therapy. Mol. Cancer 2022, 21, 99. [Google Scholar] [CrossRef]
- Bricelj, A.; Steinebach, C.; Kuchta, R.; Gütschow, M.; Sosič, I. E3 Ligase Ligands in Successful PROTACs: An Overview of Syntheses and Linker Attachment Points. Front. Chem. 2021, 9, 707317. [Google Scholar] [CrossRef] [PubMed]
- Gadd, M.S.; Testa, A.; Lucas, X.; Chan, K.-H.; Chen, W.; Lamont, D.J.; Zengerle, M.; Ciulli, A. Structural basis of PROTAC cooperative recognition for selective protein degradation. Nat. Chem. Biol. 2017, 13, 514–521. [Google Scholar] [CrossRef]
- Kramer, L.T.; Zhang, X. Expanding the landscape of E3 ligases for targeted protein degradation. Curr. Res. Chem. Biol. 2022, 2, 100020. [Google Scholar] [CrossRef]
- Lebraud, H.; Wright, D.J.; Johnson, C.N.; Heightman, T.D. Protein Degradation by In-Cell Self-Assembly of Proteolysis Targeting Chimeras. ACS Cent. Sci. 2016, 2, 927–934. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Wei, M.; Zhao, R.; Cao, Y.; Wei, Y.; Li, M.; Dong, Z.; Liu, Y.; Ruan, H.; Li, Y.; Cao, S.; et al. First orally bioavailable prodrug of proteolysis targeting chimera (PROTAC) degrades cyclin-dependent kinases 2/4/6 in vivo. Eur. J. Med. Chem. 2021, 209, 112903. [Google Scholar] [CrossRef] [PubMed]
- Matsson, P.; Kihlberg, J. How Big Is Too Big for Cell Permeability? J. Med. Chem. 2017, 60, 1662–1664. [Google Scholar] [CrossRef] [Green Version]
- Schneekloth, J.S.; Fonseca, F.N.; Koldobskiy, M.; Mandal, A.; Deshaies, R.; Sakamoto, K.; Crews, C.M. Chemical genetic control of protein levels: Selective in vivo targeted degradation. J. Am. Chem. Soc. 2004, 126, 3748–3754. [Google Scholar] [CrossRef] [Green Version]
- Salerno, A.; Seghetti, F.; Caciolla, J.; Uliassi, E.; Testi, E.; Guardigni, M.; Roberti, M.; Milelli, A.; Bolognesi, M.L. Enriching Proteolysis Targeting Chimeras with a Second Modality: When Two Are Better Than One. J. Med. Chem. 2022, 65, 9507–9530. [Google Scholar] [CrossRef] [PubMed]
- Zeng, S.; Zhang, H.; Shen, Z.; Huang, W. Photopharmacology of Proteolysis-Targeting Chimeras: A New Frontier for Drug Discovery. Front Chem. 2021, 10, 9:639176. [Google Scholar] [CrossRef]
- Silva, J.M.; Silva, E.; Reis, R.L. Light-triggered release of photocaged therapeutics—Where are we now? J. Control. Release 2019, 298, 154–176. [Google Scholar] [CrossRef]
- Fenno, L.; Yizhar, O.; Deisseroth, K. The development and application of optogenetics. Annu. Rev. Neurosci. 2011, 34, 389–412. [Google Scholar] [CrossRef] [PubMed]
- Lerch, M.M.; Hansen, M.J.; van Dam, G.M.; Szymanski, W.; Feringa, B.L. Emerging Targets in Photopharmacology. Angew. Chem. Int. Ed. 2016, 55, 10978–10999. [Google Scholar] [CrossRef] [PubMed]
- Hüll, K.; Morstein, J.; Trauner, D. In Vivo Photopharmacology. Chem. Rev. 2018, 118, 10710–10747. [Google Scholar] [CrossRef] [PubMed]
- Wang, Y.; Han, L.; Liu, F.; Yang, F.; Jiang, X.; Sun, H.; Feng, F.; Xue, J.; Liu, W. Targeted degradation of anaplastic lymphoma kinase by gold nanoparticle-based multi-headed proteolysis targeting chimeras. Colloids Surf. B: Biointerfaces 2020, 188, 110795. [Google Scholar] [CrossRef]
- Gao, J.; Hou, B.; Zhu, Q.; Yang, L.; Jiang, X.; Zou, Z.; Li, X.; Xu, T.; Zheng, M.; Chen, Y.-H.; et al. Engineered bioorthogonal POLY-PROTAC nanoparticles for tumour-specific protein degradation and precise cancer therapy. Nat. Commun. 2022, 13, 4318. [Google Scholar] [CrossRef]
- Juan, A.; del Mar Noblejas-López, M.; Arenas-Moreira, M.; Alonso-Moreno, C.; Ocaña, A. Options to Improve the Action of PROTACs in Cancer: Development of Controlled Delivery Nanoparticles. Front. Cell Dev. Biol. 2022, 9, 3912. [Google Scholar] [CrossRef]
- Maneiro, M.; Forte, N.; Shchepinova, M.M.; Kounde, C.S.; Chudasama, V.; Baker, J.R.; Tate, E.W. Antibody—PROTAC Conjugates Enable HER2-Dependent Targeted Protein Degradation of BRD4. ACS Chem. Biol. 2020, 15, 1306–1312. [Google Scholar] [CrossRef]
- Pillow, T.H.; Adhikari, P.; Blake, R.A.; Chen, J.; Del Rosario, G.; Deshmukh, G.; Figueroa, I.; Gascoigne, K.E.; Kamath, A.V.; Kaufman, S.; et al. Antibody Conjugation of a Chimeric BET Degrader Enables in vivo Activity. ChemMedChem 2020, 15, 17–25. [Google Scholar] [CrossRef] [Green Version]
- Dragovich, P.S.; Adhikari, P.; Blake, R.A.; Blaquiere, N.; Chen, J.; Cheng, Y.-X.; den Besten, W.; Han, J.; Hartman, S.J.; He, J.; et al. Antibody-mediated delivery of chimeric protein degraders which target estrogen receptor alpha (ERα). Bioorg. Med. Chem. Lett. 2020, 30, 126907. [Google Scholar] [CrossRef]
- Dragovich, P.S.; Pillow, T.H.; Blake, R.A.; Sadowsky, J.D.; Adaligil, E.; Adhikari, P.; Bhakta, S.; Blaquiere, N.; Chen, J.; Dela Cruz-Chuh, J.; et al. Antibody-Mediated Delivery of Chimeric BRD4 Degraders. Part 1: Exploration of Antibody Linker, Payload Loading, and Payload Molecular Properties. J. Med. Chem. 2021, 64, 2534–2575. [Google Scholar] [CrossRef]
- Dragovich, P.S.; Pillow, T.H.; Blake, R.A.; Sadowsky, J.D.; Adaligil, E.; Adhikari, P.; Chen, J.; Corr, N.; Cruz-Chuh, J.D.; Del Rosario, G.; et al. Antibody-Mediated Delivery of Chimeric BRD4 Degraders. Part 2: Improvement of In Vitro Antiproliferation Activity and In Vivo Antitumor Efficacy. J. Med. Chem. 2021, 64, 2576–2607. [Google Scholar] [CrossRef] [PubMed]
- Buckley, D.L.; Raina, K.; Darricarrere, N.; Hines, J.; Gustafson, J.L.; Smith, I.E.; Miah, A.H.; Harling, J.D.; Crews, C.M. HaloPROTACS: Use of Small Molecule PROTACs to Induce Degradation of HaloTag Fusion Proteins. ACS Chem. Biol. 2015, 10, 1831–1837. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Tovell, H.; Testa, A.; Maniaci, C.; Zhou, H.; Prescott, A.R.; Macartney, T.; Ciulli, A.; Alessi, D.R. Rapid and Reversible Knockdown of Endogenously Tagged Endosomal Proteins via an Optimized HaloPROTAC Degrader. ACS Chem. Biol. 2019, 14, 882–892. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Nabet, B.; Roberts, J.M.; Buckley, D.L.; Paulk, J.; Dastjerdi, S.; Yang, A.; Leggett, A.L.; Erb, M.A.; Lawlor, M.A.; Souza, A.; et al. The dTAG system for immediate and target-specific protein degradation. Nat. Chem. Biol. 2018, 14, 431–441. [Google Scholar] [CrossRef]
- Nabet, B.; Ferguson, F.M.; Seong, B.K.A.; Kuljanin, M.; Leggett, A.L.; Mohardt, M.L.; Robichaud, A.; Conway, A.S.; Buckley, D.L.; Mancias, J.D.; et al. Rapid and direct control of target protein levels with VHL-recruiting dTAG molecules. Nat. Commun. 2020, 11, 4687. [Google Scholar] [CrossRef]
- Nowak, R.P.; Xiong, Y.; Kirmani, N.; Kalabathula, J.; Donovan, K.A.; Eleuteri, N.A.; Yuan, J.C.; Fischer, E.S. Structure-Guided Design of a “Bump-and-Hole” Bromodomain-Based Degradation Tag. J. Med. Chem. 2021, 64, 11637–11650. [Google Scholar] [CrossRef]
- Veits, G.K.; Henderson, C.S.; Vogelaar, A.; Eron, S.J.; Lee, L.; Hart, A.; Deibler, R.W.; Baddour, J.; Elam, W.A.; Agafonov, R.V.; et al. Development of an AchillesTAG degradation system and its application to control CAR-T activity. Curr. Res. Chem. Biol. 2021, 1, 100010. [Google Scholar] [CrossRef]
- Adkins, S. CAR T-Cell Therapy: Adverse Events and Management. J. Adv. Pract. Oncol. 2019, 10, 21–28. [Google Scholar] [CrossRef]
- Budde, L.E.; Berger, C.; Lin, Y.; Wang, J.; Lin, X.; Frayo, S.E.; Brouns, S.A.; Spencer, D.M.; Till, B.G.; Jensen, M.C.; et al. Combining a CD20 Chimeric Antigen Receptor and an Inducible Caspase 9 Suicide Switch to Improve the Efficacy and Safety of T Cell Adoptive Immunotherapy for Lymphoma. PLoS ONE 2013, 8, e82742. [Google Scholar] [CrossRef] [Green Version]
- Tae, H.S.; Sundberg, T.B.; Neklesa, T.K.; Noblin, D.J.; Gustafson, J.L.; Roth, A.G.; Raina, K.; Crews, C.M. Identification of hydrophobic tags for the degradation of stabilized proteins. ChemBioChem 2012, 13, 538–541. [Google Scholar] [CrossRef]
- Xie, T.; Lim, S.M.; Westover, K.D.; Dodge, M.E.; Ercan, D.; Ficarro, S.B.; Udayakumar, D.; Gurbani, D.; Tae, H.S.; Riddle, S.M.; et al. Pharmacological targeting of the pseudokinase Her3. Nat. Chem. Biol. 2014, 10, 1006–1012. [Google Scholar] [CrossRef] [PubMed]
- Choi, S.R.; Wang, H.M.; Shin, M.H.; Lim, H.-S. Hydrophobic Tagging-Mediated Degradation of Transcription Coactivator SRC-1. Int. J. Mol. Sci. 2021, 22, 6407. [Google Scholar] [CrossRef] [PubMed]
- Ma, A.; Stratikopoulos, E.; Park, K.S.; Wei, J.; Martin, T.C.; Yang, X.; Schwarz, M.; Leshchenko, V.; Rialdi, A.; Dale, B.; et al. Discovery of a first-in-class EZH2 selective degrader. Nat. Chem. Biol. 2020, 16, 214. [Google Scholar] [CrossRef]
- Gustafson, J.L.; Neklesa, T.K.; Cox, C.S.; Roth, A.G.; Buckley, D.L.; Tae, H.S.; Sundberg, T.B.; Stagg, D.B.; Hines, J.; McDonnell, D.P.; et al. Small-Molecule-Mediated Degradation of the Androgen Receptor through Hydrophobic Tagging. Angew. Chem. Int. Ed. 2015, 54, 9659–9662. [Google Scholar] [CrossRef] [PubMed]
- Maniaci, C.; Hughes, S.J.; Testa, A.; Chen, W.; Lamont, D.J.; Rocha, S.; Alessi, D.R.; Romeo, R.; Ciulli, A. Homo-PROTACs: Bivalent small-molecule dimerizers of the VHL E3 ubiquitin ligase to induce self-degradation. Nat. Commun. 2017, 8, 830. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Steinebach, C.; Lindner, S.; Udeshi, N.D.; Mani, D.C.; Kehm, H.; Köpff, S.; Carr, S.A.; Gütschow, M.; Krönke, J. Homo-PROTACs for the Chemical Knockdown of Cereblon. ACS Chem. Biol. 2018, 13, 2771–2782. [Google Scholar] [CrossRef]
- Steinebach, C.; Kehm, H.; Lindner, S.; Vu, L.P.; Köpff, S.; Mármol, Á.L.; Weiler, C.; Wagner, K.G.; Reichenzeller, M.; Krönke, J.; et al. PROTAC-mediated crosstalk between E3 ligases. Chem. Commun. 2019, 55, 1821–1824. [Google Scholar] [CrossRef]
- He, S.; Ma, J.; Fang, Y.; Liu, Y.; Wu, S.; Dong, G.; Wang, W.; Sheng, C. Homo-PROTAC mediated suicide of MDM2 to treat non-small cell lung cancer. Acta Pharm. Sin. B 2021, 11, 1617–1628. [Google Scholar] [CrossRef]
- Wagner, A.J.; Banerji, U.; Mahipal, A.; Somaiah, N.; Hirsch, H.; Fancourt, C.; Johnson-Levonas, A.O.; Lam, R.; Meister, A.K.; Russo, G.; et al. Phase I Trial of the Human Double Minute 2 Inhibitor MK-8242 in Patients with Advanced Solid Tumors. J. Clin. Oncol. 2017, 35, 1304–1311. [Google Scholar] [CrossRef]
- Iancu-Rubin, C.; Mosoyan, G.; Glenn, K.; Gordon, R.E.; Nichols, G.L.; Hoffman, R. Activation of p53 by the MDM2 inhibitor RG7112 impairs thrombopoiesis. Exp. Hematol. 2014, 42, 137–145.e5. [Google Scholar] [CrossRef]
- Ghidini, A.; Cléry, A.; Halloy, F.; Allain, F.H.T.; Hall, J. RNA-PROTACs: Degraders of RNA-Binding Proteins. Angew. Chem. Int. Ed. 2021, 60, 3163–3169. [Google Scholar] [CrossRef] [PubMed]
- Hong, S. RNA Binding Protein as an Emerging Therapeutic Target for Cancer Prevention and Treatment. Eur. J. Cancer Prev. 2017, 22, 203–210. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Gerstberger, S.; Hafner, M.; Tuschl, T. A census of human RNA-binding proteins. Nat. Rev. Genet. 2014, 15, 829–845. [Google Scholar] [CrossRef] [PubMed]
- Wang, E.T.; Taliaferro, J.M.; Lee, J.-A.; Sudhakaran, I.P.; Rossoll, W.; Gross, C.; Moss, K.R.; Bassell, G.J. Dysregulation of mRNA Localization and Translation in Genetic Disease. J. Neurosci. 2016, 36, 11418–11426. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Liu, J.; Chen, H.; Kaniskan, H.Ü.; Xie, L.; Chen, X.; Jin, J.; Wei, W. TF-PROTACs Enable Targeted Degradation of Transcription Factors. J. Am. Chem. Soc. 2021, 143, 8902–8910. [Google Scholar] [CrossRef] [PubMed]
- Li, X.; Pu, W.; Chen, S.; Peng, Y. Therapeutic targeting of RNA-binding protein by RNA-PROTAC. Mol. Ther. 2021, 29, 1940–1942. [Google Scholar] [CrossRef] [PubMed]
- Roberts, T.C.; Langer, R.; Wood, M.J.A. Advances in oligonucleotide drug delivery. Nat. Rev. Drug Discov. 2020, 19, 673–694. [Google Scholar] [CrossRef]
- Samarasinghe, K.T.G.; Jaime-Figueroa, S.; Burgess, M.; Nalawansha, D.A.; Dai, K.; Hu, Z.; Bebenek, A.; Holley, S.A.; Crews, C.M. Targeted degradation of transcription factors by TRAFTACs: TRAnscription Factor TArgeting Chimeras. Cell Chem. Biol. 2021, 28, 648–661.e5. [Google Scholar] [CrossRef]
- Ng, C.S.C.; Banik, S.M. Taming transcription factors with TRAFTACs. Cell Chem. Biol. 2021, 28, 588–590. [Google Scholar] [CrossRef]
- Shao, J.; Yan, Y.; Ding, D.; Wang, D.; He, Y.; Pan, Y.; Yan, W.; Kharbanda, A.; Li, H.; Huang, H. Destruction of DNA-binding proteins by programmable O’PROTAC: Oligonucleotide-based PROTAC. Adv. Sci. (Weinh). 2021, 20, e2102555. [Google Scholar] [CrossRef]
- Perner, S.; Mosquera, J.-M.; Demichelis, F.; Hofer, M.D.; Paris, P.L.; Simko, J.; Collins, C.; Bismar, T.A.; Chinnaiyan, A.M.; De Marzo, A.M.; et al. TMPRSS2-ERG fusion prostate cancer: An early molecular event associated with invasion. Am. J. Surg. Pathol. 2007, 31, 882–888. [Google Scholar] [CrossRef] [PubMed]
- Balasubramanian, S.; Hurley, L.H.; Neidle, S. Targeting G-quadruplexes in gene promoters: A novel anticancer strategy? Nat. Rev. Drug Discov. 2011, 10, 261–275. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Patil, K.M.; Chin, D.; Seah, H.L.; Shi, Q.; Lim, K.W.; Phan, A.T. G4-PROTAC: Targeted degradation of a G-quadruplex binding protein. Chem. Commun. 2021, 57, 12816–12819. [Google Scholar] [CrossRef] [PubMed]
- Thiel, K.W.; Giangrande, P.H. Intracellular delivery of RNA-based therapeutics using aptamers. Ther. Deliv. 2010, 1, 849–861. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Zhou, J.; Rossi, J. Aptamers as targeted therapeutics: Current potential and challenges. Nat. Rev. Drug Discov. 2017, 16, 181–202. [Google Scholar] [CrossRef] [Green Version]
- Rosenberg, J.E.; Bambury, R.M.; Van Allen, E.M.; Drabkin, H.A.; Lara, P.N.; Harzstark, A.L.; Wagle, N.; Figlin, R.A.; Smith, G.W.; Garraway, L.A.; et al. A phase II trial of AS1411 (a novel nucleolin-targeted DNA aptamer) in metastatic renal cell carcinoma. Investig. New Drugs 2014, 32, 178–187. [Google Scholar] [CrossRef]
- Yazdian-Robati, R.; Bayat, P.; Oroojalian, F.; Zargari, M.; Ramezani, M.; Taghdisi, S.M.; Abnous, K. Therapeutic applications of AS1411 aptamer, an update review. Int. J. Biol. Macromol. 2020, 155, 1420–1431. [Google Scholar] [CrossRef]
- He, S.; Gao, F.; Ma, J.; Ma, H.; Dong, G.; Sheng, C. Aptamer-PROTAC Conjugates (APCs) for Tumor-Specific Targeting in Breast Cancer. Angew. Chem. Int. Ed. 2021, 60, 23299–23305. [Google Scholar] [CrossRef]
- Zhang, L.; Li, L.; Wang, X.; Liu, H.; Zhang, Y.; Xie, T.; Zhang, H.; Li, X.; Peng, T.; Sun, X.; et al. Development of a novel PROTAC using the nucleic acid aptamer as a targeting ligand for tumor selective degradation of nucleolin. Mol. Ther. Nucleic Acids 2022, 30, 66–79. [Google Scholar] [CrossRef] [PubMed]
- Zhang, Y.; Erb, M.A. Enabling cancer target validation with genetically encoded systems for ligand-induced protein degradation. Curr. Res. Chem. Biol. 2021, 1, 100011. [Google Scholar] [CrossRef]
- Schreiber, S.L. The Rise of Molecular Glues. Cell 2021, 184, 3–9. [Google Scholar] [CrossRef] [PubMed]
- Geiger, T.M.; Schäfer, S.C.; Dreizler, J.K.; Walz, M.; Hausch, F. Clues to molecular glues. Curr. Res. Chem. Biol. 2022, 2, 100018. [Google Scholar] [CrossRef]
- Tan, X.; Calderon-Villalobos, L.I.A.; Sharon, M.; Zheng, C.; Robinson, C.V.; Estelle, M.; Zheng, N. Mechanism of auxin perception by the TIR1 ubiquitin ligase. Nature 2007, 446, 640–645. [Google Scholar] [CrossRef]
- Nishimura, K.; Fukagawa, T.; Takisawa, H.; Kakimoto, T.; Kanemaki, M. An auxin-based degron system for the rapid depletion of proteins in nonplant cells. Nat. Method. 2009, 6, 917–922. [Google Scholar] [CrossRef] [PubMed]
- Zhang, Y.; Hsu, C.-P.; Lu, J.-F.; Kuchimanchi, M.; Sun, Y.-N.; Ma, J.; Xu, G.; Zhang, Y.; Xu, Y.; Weidner, M.; et al. FLT3 and CDK4/6 inhibitors: Signaling mechanisms and tumor burden in subcutaneous and orthotopic mouse models of acute myeloid leukemia. J. Pharmacokinet. Pharmacodyn. 2014, 41, 675–691. [Google Scholar] [CrossRef] [Green Version]
- Krönke, J.; Udeshi, N.D.; Narla, A.; Grauman, P.; Hurst, S.N.; McConkey, M.; Svinkina, T.; Heckl, D.; Comer, E.; Li, X.; et al. Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells. Science 2014, 343, 301–305. [Google Scholar] [CrossRef] [Green Version]
- Jan, M.; Sperling, A.S.; Ebert, B.L. Cancer therapies based on targeted protein degradation—Lessons learned with lenalidomide. Nat. Rev. Clin. Oncol. 2021, 18, 401–417. [Google Scholar] [CrossRef]
- Krönke, J.; Fink, E.C.; Hollenbach, P.W.; MacBeth, K.J.; Hurst, S.N.; Udeshi, N.D.; Chamberlain, P.P.; Mani, D.R.; Man, H.W.; Gandhi, A.K.; et al. Lenalidomide induces ubiquitination and degradation of CK1α in del(5q) MDS. Nature 2015, 523, 183–188. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Sievers, Q.L.; Petzold, G.; Bunker, R.D.; Renneville, A.; Słabicki, M.; Liddicoat, B.J.; Abdulrahman, W.; Mikkelsen, T.; Ebert, B.L.; Thomä, N.H. Defining the human C2H2 zinc finger degrome targeted by thalidomide analogs through CRBN. Science 2018, 362, eaat0572. [Google Scholar] [CrossRef] [Green Version]
- Gao, S.; Wang, S.; Song, Y. Novel immunomodulatory drugs and neo-substrates. Biomark. Res. 2020, 8, 2. [Google Scholar] [CrossRef]
- Carbonneau, S.; Sharma, S.; Peng, L.; Rajan, V.; Hainzl, D.; Henault, M.; Yang, C.; Hale, J.; Shulok, J.; Tallarico, J.; et al. An IMiD-inducible degron provides reversible regulation for chimeric antigen receptor expression and activity. Cell Chem. Biol. 2021, 28, 802–812.e6. [Google Scholar] [CrossRef] [PubMed]
- Koduri, V.; McBrayer, S.K.; Liberzon, E.; Wang, A.C.; Briggs, K.J.; Cho, H.; Kaelin, W.G. Peptidic degron for IMiD-induced degradation of heterologous proteins. Proc. Natl. Acad. Sci. USA 2019, 116, 2539–2544. [Google Scholar] [CrossRef] [Green Version]
- Yamanaka, S.; Shoya, Y.; Matsuoka, S.; Nishida-Fukuda, H.; Shibata, N.; Sawasaki, T. An IMiD-induced SALL4 degron system for selective degradation of target proteins. Commun. Biol. 2020, 3, 515. [Google Scholar] [CrossRef]
- Bussiere, D.E.; Xie, L.; Srinivas, H.; Shu, W.; Burke, A.; Be, C.; Zhao, J.; Godbole, A.; King, D.; Karki, R.G.; et al. Structural basis of indisulam-mediated RBM39 recruitment to DCAF15 E3 ligase complex. Nat. Chem. Biol. 2020, 16, 15–23. [Google Scholar] [CrossRef]
- Faust, T.B.; Yoon, H.; Nowak, R.P.; Donovan, K.A.; Li, Z.; Cai, Q.; Eleuteri, N.A.; Zhang, T.; Gray, N.S.; Fischer, E.S. Structural complementarity facilitates E7820-mediated degradation of RBM39 by DCAF15. Nat. Chem. Biol. 2020, 16, 7–14. [Google Scholar] [CrossRef] [PubMed]
- Du, X.; Volkov, O.A.; Czerwinski, R.M.; Tan, H.; Huerta, C.; Morton, E.R.; Rizzi, J.P.; Wehn, P.M.; Xu, R.; Nijhawan, D.; et al. Structural Basis and Kinetic Pathway of RBM39 Recruitment to DCAF15 by a Sulfonamide Molecular Glue E7820. Structure 2019, 27, 1625–1633.e3. [Google Scholar] [CrossRef] [PubMed]
- Simonetta, K.R.; Taygerly, J.; Boyle, K.; Basham, S.E.; Padovani, C.; Lou, Y.; Cummins, T.J.; Yung, S.L.; von Soly, S.K.; Kayser, F.; et al. Prospective discovery of small molecule enhancers of an E3 ligase-substrate interaction. Nat. Commun. 2019, 10, 1402. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Słabicki, M.; Kozicka, Z.; Petzold, G.; Li, Y.-D.; Manojkumar, M.; Bunker, R.D.; Donovan, K.A.; Sievers, Q.L.; Koeppel, J.; Suchyta, D.; et al. The CDK inhibitor CR8 acts as a molecular glue degrader that depletes cyclin K. Nature 2020, 585, 293–297. [Google Scholar] [CrossRef] [PubMed]
- Mayor-Ruiz, C.; Bauer, S.; Brand, M.; Kozicka, Z.; Siklos, M.; Imrichova, H.; Kaltheuner, I.H.; Hahn, E.; Seiler, K.; Koren, A.; et al. Rational discovery of molecular glue degraders via scalable chemical profiling. Nat. Chem. Biol. 2020, 16, 1199–1207. [Google Scholar] [CrossRef] [PubMed]
- Słabicki, M.; Yoon, H.; Koeppel, J.; Nitsch, L.; Burman, S.S.R.; Di Genua, C.; Donovan, K.A.; Sperling, A.S.; Hunkeler, M.; Tsai, J.M.; et al. Small-molecule-induced polymerization triggers degradation of BCL6. Nature 2020, 588, 164–168. [Google Scholar] [CrossRef]
- Bellenie, B.R.; Cheung, K.-M.J.; Varela, A.; Pierrat, O.A.; Collie, G.W.; Box, G.M.; Bright, M.D.; Gowan, S.; Hayes, A.; Rodrigues, M.J.; et al. Achieving In Vivo Target Depletion through the Discovery and Optimization of Benzimidazolone BCL6 Degraders. J. Med. Chem. 2020, 63, 4047–4068. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Li, H.; Dong, J.; Cai, M.; Xu, Z.; Cheng, X.D.; Qin, J.J. Protein degradation technology: A strategic paradigm shift in drug discovery. J. Hematol. Oncol. 2021, 14, 138. [Google Scholar] [CrossRef]
- Naito, M.; Ohoka, N.; Shibata, N. SNIPERs—Hijacking IAP activity to induce protein degradation. Drug Discov. Today Technol. 2019, 31, 35–42. [Google Scholar] [CrossRef] [PubMed]
- Naito, M. Targeted protein degradation and drug discovery. J. Biochem. 2022, 172, 61–69. [Google Scholar] [CrossRef]
- Ma, Z.; Ji, Y.; Yu, Y.; Liang, D. Specific non-genetic IAP-based protein erasers (SNIPERs) as a potential therapeutic strategy. Eur. J. Med. Chem. 2021, 216, 113247. [Google Scholar] [CrossRef] [PubMed]
- Takahashi, D.; Moriyama, J.; Nakamura, T.; Miki, E.; Takahashi, E.; Sato, A.; Akaike, T.; Itto-Nakama, K.; Arimoto, H. AUTACs: Cargo-Specific Degraders Using Selective Autophagy. Mol. Cell 2019, 76, 797–810.e10. [Google Scholar] [CrossRef]
- Takahashi, D.; Arimoto, H. Targeting selective autophagy by AUTAC degraders. Autophagy 2020, 16, 765–766. [Google Scholar] [CrossRef]
- Li, Z.; Wang, C.; Wang, Z.; Zhu, C.; Li, J.; Sha, T.; Ma, L.; Gao, C.; Yang, Y.; Sun, Y.; et al. Allele-selective lowering of mutant HTT protein by HTT-LC3 linker compounds. Nature 2019, 575, 203–209. [Google Scholar] [CrossRef]
- Fu, Y.; Chen, N.; Wang, Z.; Luo, S.; Ding, Y.; Lu, B. Degradation of lipid droplets by chimeric autophagy-tethering compounds. Cell Res. 2021, 31, 965–979. [Google Scholar] [CrossRef]
- Ji, C.H.; Kim, H.Y.; Lee, M.J.; Heo, A.J.; Park, D.Y.; Lim, S.; Shin, S.; Ganipisetti, S.; Yang, W.S.; Jung, C.A.; et al. The AUTOTAC chemical biology platform for targeted protein degradation via the autophagy-lysosome system. Nat. Commun. 2022, 13, 904. [Google Scholar] [CrossRef]
- Zhao, L.; Zhao, J.; Zhong, K.; Tong, A.; Jia, D. Targeted protein degradation: Mechanisms, strategies and application. Signal Transduct. Target. Ther. 2022, 7, 113. [Google Scholar] [CrossRef] [PubMed]
- Zhang, T.; Liu, C.; Li, W.; Kuang, J.; Qiu, X.; Min, L.; Zhu, L. Targeted protein degradation in mammalian cells: A promising avenue toward future. Comput. Struct. Biotechnol. J. 2022, 20, 5477–5489. [Google Scholar] [CrossRef] [PubMed]
- Wang, H.; Yao, H.; Li, C.; Shi, H.; Lan, J.; Li, Z.; Zhang, Y.; Liang, L.; Fang, J.-Y.; Xu, J. HIP1R targets PD-L1 to lysosomal degradation to alter T cell-mediated cytotoxicity. Nat. Chem. Biol. 2019, 15, 42–50. [Google Scholar] [CrossRef]
- Banik, S.M.; Pedram, K.; Wisnovsky, S.; Ahn, G.; Riley, N.M.; Bertozzi, C.R. Lysosome-targeting chimaeras for degradation of extracellular proteins. Nature 2020, 584, 291–297. [Google Scholar] [CrossRef]
- Ahn, G.; Banik, S.M.; Miller, C.L.; Riley, N.M.; Cochran, J.R.; Bertozzi, C.R. LYTACs that engage the asialoglycoprotein receptor for targeted protein degradation. Nat. Chem. Biol. 2021, 17, 937–946. [Google Scholar] [CrossRef] [PubMed]
- Zhou, Y.; Teng, P.; Montgomery, N.T.; Li, X.; Tang, W. Development of Triantennary N-Acetylgalactosamine Conjugates as Degraders for Extracellular Proteins. ACS Cent. Sci. 2021, 7, 499–506. [Google Scholar] [CrossRef] [PubMed]
- Caianiello, D.F.; Zhang, M.; Ray, J.D.; Howell, R.A.; Swartzel, J.C.; Branham, E.M.J.; Chirkin, E.; Sabbasani, V.R.; Gong, A.Z.; McDonald, D.M.; et al. Bifunctional small molecules that mediate the degradation of extracellular proteins. Nat. Chem. Biol. 2021, 17, 947–953. [Google Scholar] [CrossRef] [PubMed]
- Miao, Y.; Gao, Q.; Mao, M.; Zhang, C.; Yang, L.; Yang, Y.; Han, D. Bispecific Aptamer Chimeras Enable Targeted Protein Degradation on Cell Membranes. Angew. Chem. Int. Ed. 2021, 60, 11267–11271. [Google Scholar] [CrossRef]
- Cotton, A.D.; Nguyen, D.P.; Gramespacher, J.A.; Seiple, I.B.; Wells, J.A. Development of Antibody-Based PROTACs for the Degradation of the Cell-Surface Immune Checkpoint Protein PD-L1. J. Am. Chem. Soc. 2021, 143, 593–598. [Google Scholar] [CrossRef]
- Zhang, H.; Han, Y.; Yang, Y.; Lin, F.; Li, K.; Kong, L.; Liu, H.; Dang, Y.; Lin, J.; Chen, P.R. Covalently Engineered Nanobody Chimeras for Targeted Membrane Protein Degradation. J. Am. Chem. Soc. 2021, 143, 16377–16382. [Google Scholar] [CrossRef]
- Santiago, L.; Daniels, G.; Wang, D.; Deng, F.-M.; Lee, P. Wnt signaling pathway protein LEF1 in cancer, as a biomarker for prognosis and a target for treatment. Am. J. Cancer Res. 2017, 7, 1389–1406. [Google Scholar] [PubMed]
- Costales, M.G.; Matsumoto, Y.; Velagapudi, S.P.; Disney, M.D. Small Molecule Targeted Recruitment of a Nuclease to RNA. J. Am. Chem. Soc. 2018, 140, 6741–6744. [Google Scholar] [CrossRef] [PubMed]
- Costales, M.G.; Suresh, B.; Vishnu, K.; Disney, M.D. Targeted Degradation of a Hypoxia-Associated Non-coding RNA Enhances the Selectivity of a Small Molecule Interacting with RNA. Cell Chem. Biol. 2019, 26, 1180–1186.e5. [Google Scholar] [CrossRef] [PubMed]
- Dey, S.K.; Jaffrey, S.R. RIBOTACs: Small Molecules Target RNA for Degradation. Cell Chem. Biol. 2019, 26, 1047–1049. [Google Scholar] [CrossRef] [PubMed]
- Bozilovic, J.; Eing, L.; Berger, B.-T.; Adhikari, B.; Weckesser, J.; Berner, N.B.; Wilhelm, S.; Kuster, B.; Wolf, E.; Knapp, S. Novel, highly potent PROTACs targeting AURORA-A kinase. Curr. Res. Chem. Biol. 2022, 2, 100032. [Google Scholar] [CrossRef]
- Uras, I.Z.; Moll, H.P.; Casanova, E. Targeting KRAS mutant non-small-cell lung cancer: Past, present and future. Int. J. Mol. Sci. 2020, 21, 4325. [Google Scholar] [CrossRef]
- Westaby, D.; de Los Dolores Fenor de La Maza, M.; Paschalis, A.; Jimenez-Vacas, J.M.; Welti, J.; de Bono, J.; Sharp, A. A New Old Target: Androgen Receptor Signaling and Advanced Prostate Cancer. Annu. Rev. Pharmacol. Toxicol. 2022, 62, 131–153. [Google Scholar] [CrossRef]
- Neklesa, T.; Snyder, L.B.; Willard, R.R.; Vitale, N.; Pizzano, J.; Gordon, D.A.; Bookbinder, M.; Macaluso, J.; Dong, H.; Ferraro, C.; et al. ARV-110: An oral androgen receptor PROTAC degrader for prostate cancer. J. Clin. Oncol. 2019, 37, 259. [Google Scholar] [CrossRef] [Green Version]
- Snyder, L.B.; Neklesa, T.K.; Chen, X.; Dong, H.; Ferraro, C.; Gordon, D.A.; Macaluso, J.; Pizzano, J.; Wang, J.; Willard, R.R.; et al. Abstract 43: Discovery of ARV-110, a first in class androgen receptor degrading PROTAC for the treatment of men with metastatic castration resistant prostate cancer. Cancer Res. 2021, 81, 43. [Google Scholar] [CrossRef]
- Xie, H.; Liu, J.; Glison, D.M.A.; Fleming, J.B. The clinical advances of proteolysis targeting chimeras in oncology. Explor. Target. Anti Tumor Ther. 2021, 2, 511–521. [Google Scholar] [CrossRef]
- Gao, X.; Burris, H.A., III; Vuky, J.; Dreicer, R.; Sartor, A.O.; Sternberg, C.N.; Percent, I.J.; Hussain, M.H.A.; Kalebasty, A.R.; Shen, J.; et al. Phase 1/2 study of ARV-110, an androgen receptor (AR) PROTAC degrader, in metastatic castration-resistant prostate cancer (mCRPC). J. Clin. Oncol. 2022, 40, 17. [Google Scholar] [CrossRef]
- Arvinas Releases Interim Clinical Data Further Demonstrating the Powerful Potential of PROTAC® Protein Degraders ARV-471 and ARV-110|Arvinas. Available online: https://ir.arvinas.com/news-releases/news-release-details/arvinas-releases-interim-clinical-data-further-demonstrating/ (accessed on 3 October 2022).
- McAndrew, N.P.; Finn, R.S. Management of ER positive metastatic breast cancer. Semin. Oncol. 2020, 47, 270–277. [Google Scholar] [CrossRef] [PubMed]
- Gonzalez, T.L.; Hancock, M.; Sun, S.; Gersch, C.L.; Larios, J.M.; David, W.; Hu, J.; Hayes, D.F.; Wang, S.; Rae, J.M. Targeted degradation of activating estrogen receptor α ligand-binding domain mutations in human breast cancer. Breast Cancer Res. Treat. 2020, 180, 611–622. [Google Scholar] [CrossRef]
- Hu, J.; Hu, B.; Wang, M.; Xu, F.; Miao, B.; Yang, C.-Y.; Wang, M.; Liu, Z.; Hayes, D.F.; Chinnaswamy, K.; et al. Discovery of ERD-308 as a Highly Potent Proteolysis Targeting Chimera (PROTAC) Degrader of Estrogen Receptor (ER). J. Med. Chem. 2019, 62, 1420–1442. [Google Scholar] [CrossRef] [PubMed]
- Flanagan, J.; Qian, Y.; Gough, S.; Andreoli, M.; Bookbinder, M.; Cadelina, G.; Bradley, J.; Rousseau, E.; Willard, R.; Pizzano, J.; et al. Abstract P5-04-18: ARV-471, an oral estrogen receptor PROTAC degrader for breast cancer. Cancer Res. 2019, 79, P5-04-18. [Google Scholar] [CrossRef]
- He, W.; Zhang, H.; Perkins, L.; Bouza, L.; Liu, K.; Qian, Y.; Fan, J. Abstract PS18-09: Novel chimeric small molecule AC682 potently degrades estrogen receptor with oral anti-tumor efficacy superior to fulvestrant. Cancer Res. 2021, 81, PS18-09. [Google Scholar] [CrossRef]
- Sun, Y.; Zhao, X.; Ding, N.; Gao, H.; Wu, Y.; Yang, Y.; Zhao, M.; Hwang, J.; Song, Y.; Liu, W.; et al. PROTAC-induced BTK degradation as a novel therapy for mutated BTK C481S induced ibrutinib-resistant B-cell malignancies. Cell Res. 2018, 28, 779–781. [Google Scholar] [CrossRef]
- Nurix Therapeutics, I. Nurix Therapeutics Reports Case Study of Patient with Aggressive Non-Hodgkin’s Lymphoma (NHL) Showing a Complete Clinical Response to NX-2127 at the 5th Annual Targeted Protein Degradation (TPD) Summit. Available online: https://www.globenewswire.com/en/news-release/2022/10/26/2541639/0/en/Nurix-Therapeutics-Reports-Case-Study-of-Patient-with-Aggressive-Non-Hodgkin-s-Lymphoma-NHL-Showing-a-Complete-Clinical-Response-to-NX-2127-at-the-5th-Annual-Targeted-Protein-Degra.html (accessed on 19 October 2022).
- Wang, C.; Zhang, Y.; Yang, S.; Chen, W.; Xing, D. PROTACs for BRDs proteins in cancer therapy: A review. J. Enzym. Inhib. Med. Chem. 2022, 37, 1694–1703. [Google Scholar] [CrossRef]
- Filippakopoulos, P.; Qi, J.; Picaud, S.; Shen, Y.; Smith, W.B.; Fedorov, O.; Morse, E.M.; Keates, T.; Hickman, T.T.; Felletar, I.; et al. Selective inhibition of BET bromodomains. Nature 2010, 468, 1067–1073. [Google Scholar] [CrossRef] [Green Version]
- Ameratunga, M.; Braña, I.; Bono, P.; Postel-Vinay, S.; Plummer, R.; Aspegren, J.; Korjamo, T.; Snapir, A.; de Bono, J.S. First-in-human Phase 1 open label study of the BET inhibitor ODM-207 in patients with selected solid tumours. Br. J. Cancer 2020, 123, 1730–1736. [Google Scholar] [CrossRef]
- Wang, L.; Chen, Y.; Mi, Y.; Qiao, J.; Jin, H.; Li, J.; Lu, Z.; Wang, Q.; Zou, Z. ATF2 inhibits ani-tumor effects of BET inhibitor in a negative feedback manner by attenuating ferroptosis. Biochem. Biophys. Res. Commun. 2021, 558, 216–223. [Google Scholar] [CrossRef] [PubMed]
- Bui, M.H.; Lin, X.; Albert, D.H.; Li, L.; Lam, L.T.; Faivre, E.J.; Warder, S.E.; Huang, X.; Wilcox, D.; Donawho, C.K.; et al. Preclinical Characterization of BET Family Bromodomain Inhibitor ABBV-075 Suggests Combination Therapeutic Strategies. Cancer Res. 2017, 77, 2976–2989. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Leal, A.S.; Williams, C.R.; Royce, D.B.; Pioli, P.A.; Sporn, M.B.; Liby, K.T. Bromodomain inhibitors, JQ1 and I-BET 762, as potential therapies for pancreatic cancer. Cancer Lett. 2017, 394, 76–87. [Google Scholar] [CrossRef]
- Doroshow, D.B.; Eder, J.P.; LoRusso, P.M. BET inhibitors: A novel epigenetic approach. Ann. Oncol. 2017, 28, 1776–1787. [Google Scholar] [CrossRef] [PubMed]
- Shapiro, G.I.; Dowlati, A.; LoRusso, P.M.; Eder, J.P.; Anderson, A.; Do, K.T.; Kagey, M.H.; Sirard, C.; Bradner, J.E.; Landau, S.B. Abstract A49: Clinically efficacy of the BET bromodomain inhibitor TEN-010 in an open-label substudy with patients with documented NUT-midline carcinoma (NMC). Mol. Cancer Ther. 2015, 14, A49. [Google Scholar] [CrossRef]
- Tontsch-Grunt, U.; Traexler, P.-E.; Baum, A.; Musa, H.; Marzin, K.; Wang, S.; Trapani, F.; Engelhardt, H.; Solca, F. Therapeutic impact of BET inhibitor BI 894999 treatment: Backtranslation from the clinic. Br. J. Cancer 2022, 127, 577–586. [Google Scholar] [CrossRef]
- Lu, J.; Qian, Y.; Altieri, M.; Dong, H.; Wang, J.; Raina, K.; Hines, J.; Winkler, J.D.; Crew, A.P.; Coleman, K.; et al. Hijacking the E3 Ubiquitin Ligase Cereblon to Efficiently Target BRD4. Chem. Biol. 2015, 22, 755–763. [Google Scholar] [CrossRef] [Green Version]
- Zengerle, M.; Chan, K.-H.; Ciulli, A. Selective Small Molecule Induced Degradation of the BET Bromodomain Protein BRD4. ACS Chem. Biol. 2015, 10, 1770–1777. [Google Scholar] [CrossRef] [Green Version]
- Kounde, C.S.; Shchepinova, M.M.; Saunders, C.N.; Muelbaier, M.; Rackham, M.D.; Harling, J.D.; Tate, E.W. A caged E3 ligase ligand for PROTAC-mediated protein degradation with light. Chem. Commun. 2020, 56, 5532–5535. [Google Scholar] [CrossRef] [PubMed]
- Peter, B.; Eisenwort, G.; Sadovnik, I.; Bauer, K.; Willmann, M.; Rülicke, T.; Berger, D.; Stefanzl, G.; Greiner, G.; Hoermann, G.; et al. BRD4 degradation blocks expression of MYC and multiple forms of stem cell resistance in Ph+ chronic myeloid leukemia. Am. J. Hematol. 2022, 97, 1215–1225. [Google Scholar] [CrossRef]
- Ranok Therapeutics Ranok Therapeutics Announces Initiation of Patient Dosing in a Phase 1/2 Clinical Trial of RNK05047, a First-in-Class BRD4-Targeting CHAMPTM Protein Degrader|Ranok Therapeutics Co., Ltd. Available online: https://ranoktherapeutics.com/newsdetail.html?aid=43 (accessed on 19 October 2022).
- Winter, G.E.; Mayer, A.; Buckley, D.L.; Erb, M.A.; Roderick, J.E.; Vittori, S.; Reyes, J.M.; di Iulio, J.; Souza, A.; Ott, C.J.; et al. BET Bromodomain Proteins Function as Master Transcription Elongation Factors Independent of CDK9 Recruitment. Mol. Cell 2017, 67, 5–18.e19. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Bai, L.; Zhou, B.; Yang, C.-Y.; Ji, J.; McEachern, D.; Przybranowski, S.; Jiang, H.; Hu, J.; Xu, F.; Zhao, Y.; et al. Targeted Degradation of BET Proteins in Triple-Negative Breast Cancer. Cancer Res. 2017, 77, 2476–2487. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Qin, C.; Hu, Y.; Zhou, B.; Fernandez-Salas, E.; Yang, C.-Y.; Liu, L.; McEachern, D.; Przybranowski, S.; Wang, M.; Stuckey, J.; et al. Discovery of QCA570 as an Exceptionally Potent and Efficacious Proteolysis Targeting Chimera (PROTAC) Degrader of the Bromodomain and Extra-Terminal (BET) Proteins Capable of Inducing Complete and Durable Tumor Regression. J. Med. Chem. 2018, 61, 6685–6704. [Google Scholar] [CrossRef] [PubMed]
- Zhang, J.; Chen, P.; Zhu, P.; Zheng, P.; Wang, T.; Wang, L.; Xu, C.; Zhou, J.; Zhang, H. Development of small-molecule BRD4 degraders based on pyrrolopyridone derivative. Bioorg. Chem. 2020, 99, 103817. [Google Scholar] [CrossRef]
- Bemis, T.A.; La Clair, J.J.; Burkart, M.D. Traceless Staudinger ligation enabled parallel synthesis of proteolysis targeting chimera linker variants. Chem. Commun. 2021, 57, 1026–1029. [Google Scholar] [CrossRef]
- Hu, R.; Wang, W.-L.; Yang, Y.-Y.; Hu, X.-T.; Wang, Q.-W.; Zuo, W.-Q.; Xu, Y.; Feng, Q.; Wang, N.-Y. Identification of a selective BRD4 PROTAC with potent antiproliferative effects in AR-positive prostate cancer based on a dual BET/PLK1 inhibitor. Eur. J. Med. Chem. 2022, 227, 113922. [Google Scholar] [CrossRef] [PubMed]
- Min, J.; Mayasundari, A.; Keramatnia, F.; Jonchere, B.; Yang, S.W.; Jarusiewicz, J.; Actis, M.; Das, S.; Young, B.; Slavish, J.; et al. Phenyl-Glutarimides: Alternative Cereblon Binders for the Design of PROTACs. Angew. Chem. Int. Ed. 2021, 60, 26663–26670. [Google Scholar] [CrossRef]
- Ohoka, N.; Ujikawa, O.; Shimokawa, K.; Sameshima, T.; Shibata, N.; Hattori, T.; Nara, H.; Cho, N.; Naito, M. Different Degradation Mechanisms of Inhibitor of Apoptosis Proteins (IAPs) by the Specific and Nongenetic IAP-Dependent Protein Eraser (SNIPER). Chem. Pharm. Bull. 2019, 67, 203–209. [Google Scholar] [CrossRef] [Green Version]
- Weisberg, E.; Chowdhury, B.; Meng, C.; Case, A.E.; Ni, W.; Garg, S.; Sattler, M.; Azab, A.K.; Sun, J.; Muz, B.; et al. BRD9 degraders as chemosensitizers in acute leukemia and multiple myeloma. Blood Cancer J. 2022, 12, 110. [Google Scholar] [CrossRef]
- C4 Therapeutics US Securities and Exchange Commission. Available online: https://www.sec.gov/Archives/edgar/data/1662579/000119312520243234/d772024ds1.htm (accessed on 4 October 2022).
- Kymera Therapeutics Receives FDA Orphan Drug Designation. Available online: https://www.globenewswire.com/en/news-release/2022/06/01/2454307/0/en/Kymera-Therapeutics-Receives-FDA-Orphan-Drug-Designation-for-KT-333-a-First-in-Class-Investigational-STAT3-Degrader-for-the-Treatment-of-Peripheral-T-Cell-Lymphoma.html (accessed on 4 October 2022).
- Khan, S.; Zhang, X.; Lv, D.; Zhang, Q.; He, Y.; Zhang, P.; Liu, X.; Thummuri, D.; Yuan, Y.; Wiegand, J.S.; et al. A selective BCL-XL PROTAC degrader achieves safe and potent antitumor activity. Nat. Med. 2019, 25, 1938–1947. [Google Scholar] [CrossRef]
- He, Y.; Koch, R.; Budamagunta, V.; Zhang, P.; Zhang, X.; Khan, S.; Thummuri, D.; Ortiz, Y.T.; Zhang, X.; Lv, D.; et al. DT2216-a Bcl-xL-specific degrader is highly active against Bcl-xL-dependent T cell lymphomas. J. Hematol. Oncol. 2020, 13, 95. [Google Scholar] [CrossRef] [PubMed]
- Kolb, R.; De, U.; Khan, S.; Luo, Y.; Kim, M.-C.; Yu, H.; Wu, C.; Mo, J.; Zhang, X.; Zhang, P.; et al. Proteolysis-targeting chimera against BCL-XL destroys tumor-infiltrating regulatory T cells. Nat. Commun. 2021, 12, 1281. [Google Scholar] [CrossRef] [PubMed]
- C4 Therapeutics C4 Therapeutics Receives Study May Proceed Letter from U.S. Available online: https://www.globenewswire.com/news-release/2022/09/29/2525008/0/en/C4-Therapeutics-Receives-Study-May-Proceed-Letter-from-U-S-FDA-to-Initiate-Phase-1-2-Clinical-Trial-of-CFT1946-an-Orally-Bioavailable-BiDAC-Degrader-in-BRAF-V600-Mutant-Solid-Cance.html (accessed on 5 October 2022).
- Sowa, M.E.; Kreger, B.; Baddour, J.; Liang, Y.; Simard, J.R.; Poling, L.; Li, P.; Yu, R.; Hart, A.; Agafonov, R.V.; et al. Abstract 2158: Preclinical evaluation of CFT1946 as a selective degrader of mutant BRAF for the treatment of BRAF driven cancers. Cancer Res. 2022, 82, 2158. [Google Scholar] [CrossRef]
- Cullgen Announces Chinese NMPA Allowance of Investigational New Drug Application of TRK Degrader to Begin Clinical Trials. Available online: https://www.cullgen.com/news (accessed on 18 October 2022).
- C4 Therapeutics C4 Therapeutics Presents Pre-clinical Data on CFT8919, A Selective Degrader of EGFR L858R, at Keystone Symposium on Targeted Protein Degradation—C4 Therapeutics. Available online: https://ir.c4therapeutics.com/news-releases/news-release-details/c4-therapeutics-presents-pre-clinical-data-cft8919-selective/ (accessed on 5 October 2022).
- Chutake, Y.; Mayo, M.; Chen, D.; Enerson, B.; Cho, P.; Filiatrault, J.; Brown, C.; Placke, M.; Adams, M.; Karnik, R.; et al. Abstract 3934: KT-253, a highly potent and selective heterobifunctional MDM2 degrader for the treatment of wildtype p53 tumors with superior potency and differentiated biological activity compared to small molecule inhibitors (SMI). Cancer Res. 2022, 82, 3934. [Google Scholar] [CrossRef]
- Hagner, P.R.; Man, H.-W.; Fontanillo, C.; Wang, M.; Couto, S.; Breider, M.; Bjorklund, C.; Havens, C.G.; Lu, G.; Rychak, E.; et al. CC-122, a pleiotropic pathway modifier, mimics an interferon response and has antitumor activity in DLBCL. Blood 2015, 126, 779–789. [Google Scholar] [CrossRef]
- Lopez-Girona, A.; Groocock, L.; Mo, Z.; Narla, R.K.; Janardhanan, P.; Wood, S.; Mendy, D.; Barnes, L.; Peng, S.; Jankeel, D.; et al. CC-99282 IS a Novel Cereblon E3 Ligase Modulator (Celmod) Agent with Potent and Broad Antitumor Activity in Preclinical Models of Diffuse Large B-Cell Lymphoma (DLBCL). Hematol. Oncol. 2021, 39, 315–316. [Google Scholar] [CrossRef]
- Carrancio, S.; Groocock, L.; Janardhanan, P.; Jankeel, D.; Galasso, R.; Guarinos, C.; Narla, R.K.; Groza, M.; Leisten, J.; Pierce, D.W.; et al. CC-99282 is a Novel Cereblon (CRBN) E3 Ligase Modulator (CELMoD) Agent with Enhanced Tumoricidal Activity in Preclinical Models of Lymphoma. Blood 2021, 138, 1200. [Google Scholar] [CrossRef]
- Carrancio, S.; Fontanillo, C.; Galasso, R.; Colombo, M.; Wood, S.; Guarinos, C.; Panjkovich, A.; Jankeel, D.; Blattler, A.; Janardhanan, P.; et al. Abstract 3932: Pathway interaction and mechanistic synergy of CC-99282, a novel cereblon E3 ligase modulator (CELMoD) agent, with enhancer of zeste homolog 2 inhibitors (EZH2is). Cancer Res. 2022, 82, 3932. [Google Scholar] [CrossRef]
- Berdeja, J.; Ailawadhi, S.; Horwitz, S.M.; Matous, J.V.; Mehta-Shah, N.; Martin, T.; Muchtar, E.; Richardson, P.G.; Richard, S.; Bhutani, M.; et al. A Phase 1 Study of CFT7455, a Novel Degrader of IKZF1/3, in Multiple Myeloma and Non-Hodgkin Lymphoma. Blood 2021, 138, 1675. [Google Scholar] [CrossRef]
- C4 Therapeutics C4 Therapeutics Presents Pre-clinical Data on CFT7455, a Novel IKZF1/3 Degrader for the Treatment of Hematologic Malignancies, at the 16th Annual International Conference on Malignant Lymphoma—C4 Therapeutics. Available online: https://ir.c4therapeutics.com/news-releases/news-release-details/c4-therapeutics-presents-pre-clinical-data-cft7455-novel-ikzf13/ (accessed on 4 October 2022).
- Hansen, J.D.; Correa, M.; Nagy, M.A.; Alexander, M.; Plantevin, V.; Grant, V.; Whitefield, B.; Huang, D.; Kercher, T.; Harris, R.; et al. Discovery of CRBN E3 Ligase Modulator CC-92480 for the Treatment of Relapsed and Refractory Multiple Myeloma. J. Med. Chem. 2020, 63, 6648–6676. [Google Scholar] [CrossRef]
- Richardson, P.G.; Ocio, E.; Raje, N.S.; Gregory, T.; White, D.; Oriol, A.; Sandhu, I.; Raab, M.-S.; LeBlanc, R.; Rodriguez, C.; et al. CC-92480, a Potent, Novel Cereblon E3 Ligase Modulator (CELMoD) Agent, in Combination with Dexamethasone (DEX) and Bortezomib (BORT) in Patients (pts) with Relapsed/Refractory Multiple Myeloma (RRMM): Preliminary Results from the Phase 1/2 Study CC-92480-MM-002. Blood 2021, 138, 2731. [Google Scholar] [CrossRef]
- Richardson, P.G.; Vangsted, A.J.; Ramasamy, K.; Trudel, S.; Martínez, J.; Mateos, M.-V.; Otero, P.R.; Lonial, S.; Popat, R.; Oriol, A.; et al. First-in-human phase I study of the novel CELMoD agent CC-92480 combined with dexamethasone (DEX) in patients (pts) with relapsed/refractory multiple myeloma (RRMM). J. Clin. Oncol. 2020, 38, 8500. [Google Scholar] [CrossRef]
- Wong, L.; Lamba, M.; Nunez, M.D.J.; Bauer, D.; Richardson, P.G.; Bahlis, N.J.; Vangsted, A.J.; Ramasamy, K.; Trudel, S.; Martinez-Lopez, J.; et al. Dose- and Schedule-Dependent Immunomodulatory Effects of the Novel CELMoD Agent CC-92480 in Patients with Relapsed/Refractory Multiple Myeloma. Blood 2020, 136, 47–48. [Google Scholar]
- Nunes, J.; McGonagle, G.A.; Eden, J.; Kiritharan, G.; Touzet, M.; Lewell, X.; Emery, J.; Eidam, H.; Harling, J.D.; Anderson, N.A. Targeting IRAK4 for Degradation with PROTACs. ACS Med. Chem. Lett. 2019, 10, 1081–1085. [Google Scholar] [CrossRef] [PubMed]
- Solomon, J.; Bonazzi, S.; d’Hennezel, E.; Beckwith, R.; Xu, L.; Fazal, A.; Magracheva, A.; Ramesh, R.; Cernijenko, A.; Antonakos, B.; et al. Targeted degradation of IKZF2 for cancer immunotherapy. Biol. Sci. 2022. [Google Scholar] [CrossRef]
- Matyskiela, M.E.; Lu, G.; Ito, T.; Pagarigan, B.; Lu, C.-C.; Miller, K.; Fang, W.; Wang, N.-Y.; Nguyen, D.; Houston, J.; et al. A novel cereblon modulator recruits GSPT1 to the CRL4(CRBN) ubiquitin ligase. Nature 2016, 535, 252–257. [Google Scholar] [CrossRef] [PubMed]
- Nishiguchi, G.; Keramatnia, F.; Min, J.; Chang, Y.; Jonchere, B.; Das, S.; Actis, M.; Price, J.; Chepyala, D.; Young, B.; et al. Identification of Potent, Selective, and Orally Bioavailable Small-Molecule GSPT1/2 Degraders from a Focused Library of Cereblon Modulators. J. Med. Chem. 2021, 64, 7296–7311. [Google Scholar] [CrossRef]
- Powell, C.E.; Du, G.; Che, J.; He, Z.; Donovan, K.A.; Yue, H.; Wang, E.S.; Nowak, R.P.; Zhang, T.; Fischer, E.S.; et al. Selective Degradation of GSPT1 by Cereblon Modulators Identified via a Focused Combinatorial Library. ACS Chem. Biol. 2020, 15, 2722–2730. [Google Scholar] [CrossRef]
- Hansen, J.D.; Correa, M.; Alexander, M.; Nagy, M.; Huang, D.; Sapienza, J.; Lu, G.; LeBrun, L.A.; Cathers, B.E.; Zhang, W.; et al. CC-90009: A Cereblon E3 Ligase Modulating Drug That Promotes Selective Degradation of GSPT1 for the Treatment of Acute Myeloid Leukemia. J. Med. Chem. 2021, 64, 1835–1843. [Google Scholar] [CrossRef]
- Gavory, G.; Ghandi, M.; d’Alessandro, A.-C.; Bonenfant, D.; Chicas, A.; Delobel, F.; Demarco, B.; Flohr, A.; King, C.; Laine, A.-L.; et al. Abstract 3929: Identification of MRT-2359 a potent, selective and orally bioavailable GSPT1-directed molecular glue degrader (MGD) for the treatment of cancers with Myc-induced translational addiction. Cancer Res. 2022, 82, 3929. [Google Scholar] [CrossRef]
- Bond, M.J.; Crews, C.M. Proteolysis targeting chimeras (PROTACs) come of age: Entering the third decade of targeted protein degradation. RSC Chem. Biol. 2021, 2, 725–742. [Google Scholar] [CrossRef] [PubMed]
- Liu, J.; Chen, H.; Liu, Y.; Shen, Y.; Meng, F.; Kaniskan, H.Ü.; Jin, J.; Wei, W. Cancer Selective Target Degradation by Folate-Caged PROTACs. J. Am. Chem. Soc. 2021, 143, 7380–7387. [Google Scholar] [CrossRef] [PubMed]
- Furie, R.A.; Hough, D.R.; Gaudy, A.; Ye, Y.; Korish, S.; Delev, N.; Weiswasser, M.; Zhan, X.; Schafer, P.H.; Werth, V.P. Iberdomide in patients with systemic lupus erythematosus: A randomised, double-blind, placebo-controlled, ascending-dose, phase 2a study. Lupus Sci. Med. 2022, 9, e000581. [Google Scholar] [CrossRef] [PubMed]
- Tomoshige, S.; Nomura, S.; Ohgane, K.; Hashimoto, Y.; Ishikawa, M. Discovery of Small Molecules that Induce the Degradation of Huntingtin. Angew. Chem. Int. Ed. 2017, 56, 11530–11533. [Google Scholar] [CrossRef] [PubMed]
- Haniff, H.S.; Tong, Y.; Liu, X.; Chen, J.L.; Suresh, B.M.; Andrews, R.J.; Peterson, J.M.; O’Leary, C.A.; Benhamou, R.I.; Moss, W.N.; et al. Targeting the SARS-CoV-2 RNA genome with small molecule binders and ribonuclease targeting chimera (RiboTAC) degraders. ACS Cent. Sci. 2020, 6, 1713–1721. [Google Scholar] [CrossRef] [PubMed]
- Cheng, B.; Ren, Y.; Cao, H.; Chen, J. Discovery of novel resorcinol diphenyl ether-based PROTAC-like molecules as dual inhibitors and degraders of PD-L1. Eur. J. Med. Chem. 2020, 199, 112377. [Google Scholar] [CrossRef]
- Wang, Y.; Zhou, Y.; Cao, S.; Sun, Y.; Dong, Z.; Li, C.; Wang, H.; Yao, Y.; Yu, H.; Song, X.; et al. In vitro and in vivo degradation of programmed cell death ligand 1 (PD-L1) by a proteolysis targeting chimera (PROTAC). Bioorgan. Chem. 2021, 111, 104833. [Google Scholar] [CrossRef] [PubMed]
- Zhang, C.; He, S.; Zeng, Z.; Cheng, P.; Pu, K. Smart Nano-PROTACs Reprogram Tumor Microenvironment for Activatable Photo-Metabolic Cancer Immunotherapy. Angew. Chem. 2022, 134, e202114957. [Google Scholar] [CrossRef]
Main Approaches To Suppress Target Of Interest | ||||
---|---|---|---|---|
PROTAC | Monoclonal Antibody | Small Molecule Inhibitor | Gene-Editing Via Nucleic Acids | |
Selectivity | +++ | ++ | + | ++ |
Route Of Administration | PO/IV/SC | IV/SC | PO/IV/SC | IV/SC |
Target Of Interest | Protein on cell surface and inside a cell | Protein on cell surface | Protein on cell surface and inside a cell | DNA or RNA |
Metabolic Stability | ++ | -/+ | ++ | -/+ |
Tissue/Cell Penetration | + | -/+ | ++ | -/+ |
Concentrations Required | Substoichiometric | N/A | Stoichiometric | N/A |
Active Binding Site | - (Can target undruggable and mutated proteins) | +++ (Can target undruggable proteins) | +++ (Cannot target mutated proteins) | - (Can target undruggable proteins) |
Inhibitory Outcome | Blockade of both enzymatic and scaffolding functions | N/A | Impaired enzymatic function | N/A |
Elimination Of POI | +++ | - | - | +++ |
Catalytic Mechanism Of Action | +++ | - | - | +++ |
Systemic Delivery | +++ | +++ | +++ | - |
Degradation Pathways | Degradation Systems | Degradable Targets | Advantages | Limitations | Highest Phase |
---|---|---|---|---|---|
Ubiquitin-proteasome | PROTAC | Intracellular proteins | In vivo, oral, improved selectivity and efficiency, does not require tight binding, catalytic and substoichiometric, definite structure and mechanism | High molecular weight, high surface area | Phase II |
Molecular glue | Intracellular proteins | Good pharmacology, specific to ligase and substrate | Mainly relies on accidential discovery | Approved | |
SNIPER | Intracellular proteins | Catalytic and substoichiometric, definite structure and mechanism | Dependent on E3 ligase IAPs | Exploratory | |
Autophagy | AUTAC | Cytoplasmic proteins, fragmented organelle | Broader targets | Lack of detailed mechanism for K63 ubiquitination | Exploratory |
ATTEC | Intracellular proteins, nonproteins | Broader targets, low molecular weight, good transmembrane activity, better pharmacokinetics | Lack of detailed interaction between LC3 and degraders, high molecular design costs, low versatility | Exploratory | |
AUTOTAC | Degradation-resistant aggregates | Broader targets | Unclarified mechanism | Exploratory | |
CMA-based | Transmembrane proteins, aggregates | High specificity | Low stability and delivery efficiency, dependent on cell penetrating peptides, limited therapeutic effects | Exploratory | |
Lysosomal | LYTAC | Extracellular proteins, membrane-associated proteins | Broader targets | Limited clinical applicability, required an antibody or a small synthetic peptide to maintain its characteristics, difficult to determine the optimal linking site, high molecular weight, induced immunogenicity | Exploratory |
MoDE-A | Extracellular proteins | Small in size, monodisperse and nonprotein based, well-tolerated immunogenicity | Relies on highly expressed ASGPR on hepatocytes | Exploratory | |
BIAC | Membrane-associated proteins | Costless and easily synthesized | In the early stages | Exploratory | |
AbTAC | Transmembrane proteins | Utilizes two specific binding sites of bispecific antibodies to recruit E3, simple optimization of binding properties, built of human parts, reduced immune response | High molecular weight | Exploratory | |
GlueTAC | Cell surface proteins | Cell-type independent degradation strategy, high specificity and efficiency | In the early stages | Exploratory | |
Ribonuclease | RIBOTAC | RNA | Favorable pharmacokinetic profile, low concentration, catalytic | High molecular weight, slow cellular uptake | Exploratory |
Time | Degrader | Target | Indication | NCT Number | Phase |
---|---|---|---|---|---|
2019 2022 | ARV-110 | AR | mCRPC | NCT03888612 NCT05177042 | Phase I/II Phase I |
2021 | ARV-766 | AR | mCRPC | NCT05067140 | Phase I |
2020 | CC-94676 | AR | mCRPC | NCT04428788 | Phase I |
2022 | HP518 | AR | mCRPC | NCT05252364 | Phase I |
2022 | AC176 | AR | mCRPC | NCT05241613 | Phase I |
2021 | DT2216 | BCL-xL | R/R malignancies | NCT04886622 | Phase I |
2022 | RNK05047 | BRD4 | Advanced solid tumors/ DLBCL | NCT05487170 | Phase I/II |
2022 | CFT8634 | BRD9 | Synovial sarcoma and SMARCB1-null tumors | NCT05355753 | Phase I/II |
2021 | FHD-609 | BRD9 | Advanced synovial sarcoma or advanced SMARCB1-null tumors | NCT04965753 | Phase I |
2021 | NX-2127 | BTK | R/R B-cell malignancies | NCT04830137 | Phase I |
2021 | NX-5948 | BTK | R/R B-cell malignancies | NCT05131022 | Phase I |
2021 2022 | BGB-16673 | BTK | B-cell malignancies | NCT05006716 NCT05294731 | Phase I Phase I |
2021 | HSK29116 | BTK | R/R B-cell malignancies | NCT04861779 | Phase I |
2019 2022 2022 2022 2022 | ARV-471 | ER | ER+/HER2- locally advanced or metastatic breast cancer | NCT04072952 NCT05501769 NCT05463952 NCT05549505 NCT05548127 | Phase I/II Phase I Phase I Phase II Phase I/II |
2021 2022 | AC682 | ER | ER+/HER2- locally advanced or metastatic breast cancer | NCT05080842 NCT05489679 | Phase I Phase I |
2022 | KT-333 | STAT3 | Refractory lymphoma, LGL leukemia and solid tumors | NCT05225584 | Phase I |
2022 | CFT1946 | BRAFV600E | BRAF-V600E mutant solid tumors | IND | |
Planned for (2H2022) | CFT8919 | EGFRL858R | NSCLC | IND | |
Planned for (2H2022) | KT-253 | MDM2 | Liquid and solid tumors | IND | |
2022 | CG001419 | NTRK | Advanced solid tumors | IND |
Time | Degrader | Target | Indication | NCT Number | Phase |
---|---|---|---|---|---|
2011 2014 2015 2015 2015 2016 2017 2017 2017 | Avadomide | IKZF1/3 | NHL, DLBCL, hepatocellular carcinoma, B-cell CLL, MM, CLL/SLL, follicular lymphoma, advanced solid tumors and melanoma | NCT01421524 NCT02031419 NCT02417285 NCT02406742 NCT02509039 NCT02859324 NCT03310619 NCT03283202 NCT03834623 | Phase I Phase I Phase I Phase I/II Phase I Phase I/II Phase I/II Phase I/II Phase II |
2016 2020 | CC-90009 | GSPT1 | R/R AML or R/R higher-risk myelodysplastic syndromes | NCT02848001 NCT04336982 | Phase I Phase I |
2017 2019 2022 2022 2022 | CC-92480 | IKZF1/3 | R/R MM | NCT03374085 NCT03989414 NCT05372354 NCT05519085 NCT05552976 | Phase I/II Phase I/II Phase I/II Phase III Phase III |
2017 2019 2020 2021 2021 | CC-99282 | IKZF1/3 | R/R NHL and CLL/SLL | NCT03310619 NCT03930953 NCT04434196 NCT04884035 NCT05169515 | Phase I/II Phase I Phase I Phase I Phase I |
2021 | CFT7455 | IKZF1/3 | R/R NHL or MM | NCT04756726 | Phase I/II |
2019 | DKY709 | IKZF2/4 | Advanced solid tumors | NCT03891953 | Phase I |
2016 2017 2020 2020 2020 2021 2021 2021 2021 2021 2021 2021 2022 2022 2022 2022 2022 2022 2022 2022 2022 2022 | Iberdomide | IKZF1/3 | Newly diagnosed MM, R/R MM, (smoldering) plasma cell myeloma and R/R lymphoma | NCT02773030 NCT03310619 NCT04392037 NCT04464798 NCT04564703 NCT04776395 NCT04855136 NCT04998786 NCT04884035 NCT04934475 NCT04975997 NCT05169515 NCT05177536 NCT05199311 NCT05272826 NCT05289492 NCT05392946 NCT05354557 NCT05434689 NCT05527340 NCT05558319 NCT05560399 | Phase I/II Phase I/II Phase II Phase I/II Phase II Phase II Phase I/II Phase II Phase I Phase III Phase III Phase I Phase II Phase I/II Phase II Phase I/II Phase I/II Phase II Phase I/II Phase II Phase II Phase I |
2022 | KT-413 | IRAK4 | R/R B-cell NHL and MYD88 mutant and MYD88 wild-type R/R DLBCL | NCT05233033 | Phase I |
2022 | MRT-2359 | GSPT1 | NSCLC, SCLC, high-grade neuroendocrine cancer of any primary site, DLBCL and tumors with L-MYC or N-MYC amplification | NCT05546268 | Phase I/II |
Time | Degrader | Target | Indication | NCT Number | Phase |
---|---|---|---|---|---|
2017 2021 | Avadomide | IKZF1/3 | Renal insufficiency Critical illness and sepsis | NCT03097016 NCT05083520 | Phase I |
2022 | GT20029 | AR | Acne vulgaris and AGA | NCT05428449 | Phase I |
2014 2017 2019 2021 2021 | Iberdomide | IKZF1/3 | SLE SLE Hepatic impairment Renal insufficiency Critical illness and sepsis | NCT02185040 NCT03161483 NCT03824678 NCT04933747 NCT05083520 | Phase II Phase II Phase I Phase I |
2021 | KT-474 | IRAK4 | AD and HS | NCT04772885 | Phase I |
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. |
© 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Salama, A.K.A.A.; Trkulja, M.V.; Casanova, E.; Uras, I.Z. Targeted Protein Degradation: Clinical Advances in the Field of Oncology. Int. J. Mol. Sci. 2022, 23, 15440. https://doi.org/10.3390/ijms232315440
Salama AKAA, Trkulja MV, Casanova E, Uras IZ. Targeted Protein Degradation: Clinical Advances in the Field of Oncology. International Journal of Molecular Sciences. 2022; 23(23):15440. https://doi.org/10.3390/ijms232315440
Chicago/Turabian StyleSalama, Abdelrahman K. A. A., Marija V. Trkulja, Emilio Casanova, and Iris Z. Uras. 2022. "Targeted Protein Degradation: Clinical Advances in the Field of Oncology" International Journal of Molecular Sciences 23, no. 23: 15440. https://doi.org/10.3390/ijms232315440