Skip to main content

Advertisement

SpringerLink
Log in

Pan-mutant IDH1 inhibitor BAY 1436032 for effective treatment of IDH1 mutant astrocytoma in vivo

  • Original Paper
  • Published:
Acta Neuropathologica Aims and scope Submit manuscript

Abstract

Mutations in codon 132 of isocitrate dehydrogenase (IDH) 1 are frequent in diffuse glioma, acute myeloid leukemia, chondrosarcoma and intrahepatic cholangiocarcinoma. These mutations result in a neomorphic enzyme specificity which leads to a dramatic increase of intracellular d-2-hydroxyglutarate (2-HG) in tumor cells. Therefore, mutant IDH1 protein is a highly attractive target for inhibitory drugs. Here, we describe the development and properties of BAY 1436032, a pan-inhibitor of IDH1 protein with different codon 132 mutations. BAY 1436032 strongly reduces 2-HG levels in cells carrying IDH1-R132H, -R132C, -R132G, -R132S and -R132L mutations. Cells not carrying IDH mutations were unaffected. BAY 1436032 did not exhibit toxicity in vitro or in vivo. The pharmacokinetic properties of BAY 1436032 allow for oral administration. In two independent experiments, BAY 1436032 has been shown to significantly prolong survival of mice intracerebrally transplanted with human astrocytoma carrying the IDH1R132H mutation. In conclusion, we developed a pan-inhibitor targeting tumors with different IDH1R132 mutations.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Amary MF, Bacsi K, Maggiani F et al (2011) IDH1 and IDH2 mutations are frequent events in central chondrosarcoma and central and periosteal chondromas but not in other mesenchymal tumours. J Pathol 224:334–343

    Article  CAS  PubMed  Google Scholar 

  2. Balss J, Meyer J, Mueller W, Korshunov A, Hartmann C, von Deimling A (2008) Analysis of the IDH1 codon 132 mutation in brain tumors. Acta Neuropathol 116:597–602

    Article  CAS  PubMed  Google Scholar 

  3. Balss J, Pusch S, Beck A-C et al (2012) Enzymatic assay for quantitative analysis of (d)-2-hydroxyglutarate. Acta Neuropathol 124:883–891

    Article  CAS  PubMed  Google Scholar 

  4. Bleeker FE, Lamba S, Leenstra S et al (2009) IDH1 mutations at residue p. R132 (IDH1(R132)) occur frequently in high-grade gliomas but not in other solid tumors. Hum Mutat 30:7–11

    Article  CAS  PubMed  Google Scholar 

  5. Capper D, Weißert S, Balss J et al (2010) Characterization of R132H mutation specific IDH1 antibody binding in brain tumors. Brain Pathol 20:245–254

    Article  CAS  PubMed  Google Scholar 

  6. Chaturvedi A, Herbst L, Pusch S et al (2017) Pan-mutant-IDH1 inhibitor BAY1436032 is highly effective against human IDH1 mutant acute myeloid leukemia in vivo. Leukemia (accepted)

  7. Conti L, Cattaneo E (2010) Neural stem cell systems: physiological players or in vitro entities? Nat Rev Neurosci 11:176–187

    Article  CAS  PubMed  Google Scholar 

  8. Dang L, White DW, Gross S et al (2009) Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 462:739–744

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Davis M, Pragani R, Popovici-Muller J et al (2012) ML309: a potent inhibitor of R132H mutant IDH1 capable of reducing 2-hydroxyglutarate production in U87 MG glioblastoma cells. Probe Reports from the NIH Molecular Libraries Program, City

  10. Deng G, Shen J, Yin M et al (2015) Selective inhibition of mutant isocitrate dehydrogenase 1 (IDH1) via disruption of a metal binding network by an allosteric small molecule. J Biol Chem 290:762–774

    Article  CAS  PubMed  Google Scholar 

  11. Dirks PB (2010) Brain tumor stem cells: the cancer stem cell hypothesis writ large. Mol Oncol 4:420–430

    Article  PubMed  Google Scholar 

  12. Hartmann C, Meyer J, Balss J et al (2009) Type and frequency of IDH1 and IDH2 mutations are related to astrocytic and oligodendroglial differentiation and age: a study of 1010 diffuse gliomas. Acta Neuropathol 118:469–474

    Article  PubMed  Google Scholar 

  13. Ichimura K, Pearson DM, Kocialkowski S, Backlund LM, Chan R, Jones DT, Collins VP (2009) IDH1 mutations are present in the majority of common adult gliomas but are rare in primary glioblastomas. Neuro Oncol 11:341–347

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Ilkanizadeh S, Lau J, Huang M, Foster DJ, Wong R, Frantz A, Wang S, Weiss WA, Persson AI (2014) Glial progenitors as targets for transformation in glioma. Adv Cancer Res 121:1–65

    Article  PubMed  PubMed Central  Google Scholar 

  15. Laks DR, Crisman TJ, Shih MY et al (2016) Large-scale assessment of the gliomasphere model system. Neuro-oncology 18:1367–1378

    Article  PubMed  Google Scholar 

  16. Ledur PF, Liu C, He H et al (2016) Culture conditions tailored to the cell of origin are critical for maintaining native properties and tumorigenicity of glioma cells. Neuro-oncology 18:1413–1424

    Article  PubMed  Google Scholar 

  17. Lee J, Kotliarova S, Kotliarov Y et al (2006) Tumor stem cells derived from glioblastomas cultured in bFGF and EGF more closely mirror the phenotype and genotype of primary tumors than do serum-cultured cell lines. Cancer Cell 9:391–403

    Article  CAS  PubMed  Google Scholar 

  18. Li L, Paz AC, Wilky BA et al (2015) Treatment with a small molecule mutant IDH1 inhibitor suppresses tumorigenic activity and decreases production of the oncometabolite 2-hydroxyglutarate in human chondrosarcoma cells. PLoS One 10:e0133813

    Article  PubMed  PubMed Central  Google Scholar 

  19. Machida Y, Ogawara Y, Ichimura K, Matsunaga H, Takahiko S, Araki K, Kitabayashi I (2016) The mutant IDH1 inhibitor prevents growth of glioblastoma with IDH1 mutation in patient-derived xenograft (PDX) model. In: AACR (ed) Proceedings of the 107th annual meeting of the American Association for Cancer Research. AACR, pp Abstract nr 3101

  20. Mardis ER, Ding L, Dooling DJ et al (2009) Recurring mutations found by sequencing an acute myeloid leukemia genome. N Engl J Med 361:1058–1066

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Morrens J, Van Den Broeck W, Kempermann G (2012) Glial cells in adult neurogenesis. Glia 60:159–174

    Article  PubMed  Google Scholar 

  22. Noushmehr H, Weisenberger DJ, Diefes K et al (2010) Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma. Cancer Cell 17:510–522

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Okoye-Okafor UC, Bartholdy B, Cartier J et al (2015) New IDH1 mutant inhibitors for treatment of acute myeloid leukemia. Nat Chem Biol 11:878–886

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Parsons DW, Jones S, Zhang X et al (2008) An integrated genomic analysis of human glioblastoma multiforme. Science 321:1807–1812

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Paschka P, Schlenk RF, Gaidzik VI et al (2010) IDH1 and IDH2 mutations are frequent genetic alterations in acute myeloid leukemia and confer adverse prognosis in cytogenetically normal acute myeloid leukemia with NPM1 mutation without FLT3 internal tandem duplication. J Clin Oncol 28:3636–3643

    Article  CAS  PubMed  Google Scholar 

  26. Popovici-Muller J, Saunders JO, Salituro FG et al (2012) Discovery of the first potent inhibitors of mutant IDH1 that lower tumor 2-HG in vivo. ACS Med Chem Lett 3:850–855

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Pusch S, Schweizer L, Beck AC, Lehmler JM, Weissert S, Balss J, Miller AK, von Deimling A (2014) d-2-Hydroxyglutarate producing neo-enzymatic activity inversely correlates with frequency of the type of isocitrate dehydrogenase 1 mutations found in glioma. Acta Neuropathol Commun 2:19

    Article  PubMed  PubMed Central  Google Scholar 

  28. Raponi E, Agenes F, Delphin C, Assard N, Baudier J, Legraverend C, Deloulme JC (2007) S100B expression defines a state in which GFAP-expressing cells lose their neural stem cell potential and acquire a more mature developmental stage. Glia 55:165–177

    Article  PubMed  PubMed Central  Google Scholar 

  29. Rohle D, Popovici-Muller J, Palaskas N et al (2013) An inhibitor of mutant IDH1 delays growth and promotes differentiation of glioma cells. Science 340:626–630

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Suijker J, Oosting J, Koornneef A et al (2015) Inhibition of mutant IDH1 decreases D-2-HG levels without affecting tumorigenic properties of chondrosarcoma cell lines. Oncotarget 6:12505–12519

    Article  PubMed  PubMed Central  Google Scholar 

  31. Tateishi K, Wakimoto H, Iafrate AJ et al (2015) Extreme vulnerability of IDH1 mutant cancers to NAD+ depletion. Cancer Cell 28:773–784

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Wakimoto H, Tanaka S, Curry WT et al (2014) Targetable signaling pathway mutations are associated with malignant phenotype in IDH-mutant gliomas. Clin Cancer Res 20:2898–2909

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Wang F, Travins J, DeLaBarre B et al (2013) Targeted inhibition of mutant IDH2 in leukemia cells induces cellular differentiation. Science 340:622–626

    Article  CAS  PubMed  Google Scholar 

  34. Watanabe T, Nobusawa S, Kleihues P, Ohgaki H (2009) IDH1 mutations are early events in the development of astrocytomas and oligodendrogliomas. Am J Pathol 174:653–656

    Google Scholar 

  35. Wu F, Jiang H, Zheng B, Kogiso M, Yao Y, Zhou C, Li XN, Song Y (2015) Inhibition of cancer-associated mutant isocitrate dehydrogenases by 2-thiohydantoin compounds. J Med Chem 58:6899–6908

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Yan H, Parsons DW, Jin G et al (2009) IDH1 and IDH2 mutations in gliomas. N Engl J Med 360:765–773

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Zheng B, Yao Y, Liu Z, Deng L, Anglin JL, Jiang H, Prasad BV, Song Y (2013) Crystallographic investigation and selective inhibition of mutant isocitrate dehydrogenase. ACS Med Chem Lett 4:542–546

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank Ulrike Hars, Ingo P. Korndoerfer and Ismail Moarefi from Crelux GmbH for excellent structural biology support, Antje Habel and Viktoria Zeller for histological expertise, Dr. Tim Holland-Letz for biostatistics support and Dr. Ruth Wellenreuther for valuable administrative support.

Author information

Authors and Affiliations

  1. German Consortium of Translational Cancer Research (DKTK), Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany

    Stefan Pusch, Sonja Krausert, Viktoria Fischer, Jörg Balss, Daniel Schrimpf, David Capper, Felix Sahm, Jessica Eisel, Ann-Christin Beck & Andreas von Deimling

  2. Department of Neuropathology, Institute of Pathology, Ruprecht-Karls-University Heidelberg, Heidelberg, Germany

    Stefan Pusch, Viktoria Fischer, Jörg Balss, Daniel Schrimpf, David Capper, Felix Sahm & Andreas von Deimling

  3. Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany

    Martina Ott & Michael Platten

  4. Neurology Clinic and National Center for Tumor Diseases (NCT), University Hospital Heidelberg, Heidelberg, Germany

    Martina Ott, Wolfgang Wick & Michael Platten

  5. Core Facility, Small Animal Imaging Center, German Cancer Research Center (DKFZ), Heidelberg, Germany

    Manfred Jugold & Viktoria Eichwald

  6. Drug Discovery, Bayer Pharma AG, Berlin, Germany

    Stefan Kaulfuss, Olaf Panknin, Hartmut Rehwinkel, Roman C. Hillig, Judith Guenther, Luisella Toschi, Roland Neuhaus, Andrea Haegebart, Holger Hess-Stumpp & Markus Bauser

  7. Drug Discovery, Bayer Pharma AG, Wuppertal, Germany

    Katja Zimmermann

  8. Clinical Cooperation Unit Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany

    Wolfgang Wick

  9. Division of Experimental Neurosurgery, Department of Neurosurgery, University Hospital Heidelberg, Heidelberg, Germany

    Andreas Unterberg & Christel Herold-Mende

Authors
  1. Stefan Pusch
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sonja Krausert
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Viktoria Fischer
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jörg Balss
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Martina Ott
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Daniel Schrimpf
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. David Capper
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Felix Sahm
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jessica Eisel
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Ann-Christin Beck
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Manfred Jugold
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Viktoria Eichwald
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Stefan Kaulfuss
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Olaf Panknin
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Hartmut Rehwinkel
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Katja Zimmermann
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Roman C. Hillig
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Judith Guenther
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Luisella Toschi
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Roland Neuhaus
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Andrea Haegebart
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. Holger Hess-Stumpp
    View author publications

    You can also search for this author in PubMed Google Scholar

  23. Markus Bauser
    View author publications

    You can also search for this author in PubMed Google Scholar

  24. Wolfgang Wick
    View author publications

    You can also search for this author in PubMed Google Scholar

  25. Andreas Unterberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  26. Christel Herold-Mende
    View author publications

    You can also search for this author in PubMed Google Scholar

  27. Michael Platten
    View author publications

    You can also search for this author in PubMed Google Scholar

  28. Andreas von Deimling
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Andreas von Deimling.

Ethics declarations

Funding

This work was jointly funded by DKFZ and Bayer within their strategic collaboration. Viktoria Fischer is funded by the Bundesministerium für Bildung und Forschung (BMBF; Grant number 031A425A).

Conflict of interest

Stefan Pusch, Jörg Balß and Andreas von Deimling are patent holders of “Means and methods for the determination of (d)-2-hydroxyglutarate (D2HG)”, the enzymatic 2-HG assay used for 2-HG determination in this manuscript (WO2013127997A1). David Capper, Wolfgang Wick and Andreas von Deimling are patent holders of “Methods for the diagnosis and the prognosis of a brain tumor”, the IDH1R132H-specific antibody used in this manuscript (US 8367347 B2). Both patents are under the administrative supervision of the DKFZ technology transfer office. Stefan Kaulfuss, Olaf Panknin, Hartmut Rehwinkel, Katja Zimmermann, Roman C. Hillig, Judith Guenther, Luisella Toschi, Roland Neuhaus, Andrea Haegebart, Holger Hess-Stumpp and Markus Bauser are full-time employees of Bayer Pharma AG and stockholders of Bayer AG share. All other authors declare no potential conflicts of interest.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Pusch, S., Krausert, S., Fischer, V. et al. Pan-mutant IDH1 inhibitor BAY 1436032 for effective treatment of IDH1 mutant astrocytoma in vivo. Acta Neuropathol 133, 629–644 (2017). https://doi.org/10.1007/s00401-017-1677-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00401-017-1677-y

Keywords

Search

Navigation