Abstract
For decades, anticancer targeted therapies have been designed to inhibit kinases or other enzyme classes and have profoundly benefited many patients. However, novel approaches are required to target transcription factors, scaffolding proteins and other proteins central to cancer biology that typically lack catalytic activity and have remained mostly recalcitrant to drug development. The selective degradation of target proteins is an attractive approach to expand the druggable proteome, and the selective oestrogen receptor degrader fulvestrant served as an early example of this concept. Following a long and tragic history in the clinic, the immunomodulatory imide drug (IMiD) thalidomide was discovered to exert its therapeutic activity via a novel and unexpected mechanism of action: targeting proteins to an E3 ubiquitin ligase for subsequent proteasomal degradation. This discovery has paralleled and directly catalysed myriad breakthroughs in drug development, leading to the rapid maturation of generalizable chemical platforms for the targeted degradation of previously undruggable proteins. Decades of clinical experience have established front-line roles for thalidomide analogues, including lenalidomide and pomalidomide, in the treatment of haematological malignancies. With a new generation of ‘degrader’ drugs currently in development, this experience provides crucial insights into class-wide features of degraders, including a unique pharmacology, mechanisms of resistance and emerging therapeutic opportunities. Herein, we review these past experiences and discuss their application in the clinical development of novel degrader therapies.
Key points
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Thalidomide analogues including lenalidomide and pomalidomide are anticancer agents used in the treatment of multiple haematological malignancies; induction of targeted protein degradation of disease-relevant proteins is the dominant mechanism of action of these agents.
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‘Degrader’ therapeutics have a catalytic, event-driven pharmacology, and their biological effects are a summation of the polypharmacology of multiple degraded neosubstrate proteins.
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Cancers acquire resistance to thalidomide analogues by circumventing target protein degradation or by rewiring pathways downstream of target protein degradation.
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Quantitative clinical proteomic assays can be used for pharmacodynamic monitoring of degrader therapeutics.
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Molecular switches gated by degrader therapeutics can be used to control genetically engineered adoptive cell products that are being developed for anticancer immunotherapy.
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Multiple classes of degrader therapeutics are expanding the druggable proteome to include previously undruggable, noncatalytic, cancer-relevant proteins, such as transcription factors, mRNA-splicing factors and cyclins.
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Acknowledgements
The work of M.J. is supported by a NIH T32 grant to the Massachusetts General Hospital Department of Pathology (NIH-5T32CA009216-39). The work of A.S.S. is supported by NIH grant K08CA252174. The work of B.L.E is supported by NIH grants R01HL082945 and P01CA108631, the Howard Hughes Medical Institute, the Edward P. Evans Foundation, the Leukemia and Lymphoma Society and the Adelson Medical Research Foundation.
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M.J. and A.S.S. researched data for article. All authors contributed substantially to discussions of content and wrote, reviewed and edited the manuscript before submission.
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B.L.E. has received research funding from Celgene, Deerfield and Novartis, and consulting fees from GRAIL. He serves on the scientific advisory boards and holds equity in Exo Therapeutics, Neomorph Therapeutics and Skyhawk Therapeutics. M.J. and A.S.S. declare no competing interests.
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Glossary
- Molecular glue
-
A small molecule that directly bridges protein–protein interactions.
- Neosubstrate
-
A protein that is conditionally targeted to a ubiquitin ligase in the presence of a small-molecule drug.
- High-risk cytogenetic features
-
Chromosomal alterations that are associated with aggressive disease and unfavourable survival outcomes; in myeloma, these features include t(4;14), t(14;16) and del(17p) alterations.
- Antibody-dependent cellular cytotoxicity
-
(ADCC). A mechanism of cell killing that requires recognition of the antibody-bound cell by immune effector cells, such as natural killer cells.
- Activated B cell-like DLBCL
-
A subtype of diffuse large B cell lymphoma (DLBCL) that is defined by a specific transcriptional signature and is associated with high risk of relapse following standard rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) chemoimmunotherapy.
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Jan, M., Sperling, A.S. & Ebert, B.L. Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide. Nat Rev Clin Oncol 18, 401–417 (2021). https://doi.org/10.1038/s41571-021-00479-z
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DOI: https://doi.org/10.1038/s41571-021-00479-z
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