Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Acute myeloid leukemia

Pan-mutant-IDH1 inhibitor BAY1436032 is highly effective against human IDH1 mutant acute myeloid leukemia in vivo

Abstract

Neomorphic mutations in isocitrate dehydrogenase 1 (IDH1) are frequently found in several human cancer types including acute myeloid leukemia (AML) and lead to the production of high levels of the oncometabolite (R)-2-hydroxyglutarate (R-2HG). Here we report the characterization of BAY1436032, a novel pan-mutant IDH1 inhibitor, both in vitro and in vivo. BAY1436032 specifically inhibits R-2HG production and colony growth, and induces myeloid differentiation of AML cells carrying IDH1R132H, IDH1R132C, IDH1R132G, IDH1R132L and IDH1R132S mutations. In addition, the compound impacts on DNA methylation and attenuates histone hypermethylation. Oral administration of BAY1436032 led to leukemic blast clearance, myeloid differentiation, depletion of leukemic stem cells and prolonged survival in two independent patient-derived xenograft IDH1 mutant AML mouse models. Together, BAY1436032 is highly effective against all major types of IDH1 mutant AML.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Accession codes

Accessions

Gene Expression Omnibus

References

  1. 1

    Parsons DW, Jones S, Zhang X, Lin JC, Leary RJ, Angenendt P et al. An integrated genomic analysis of human glioblastoma multiforme. Science 2008; 321: 1807–1812.

    CAS  Article  Google Scholar 

  2. 2

    Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W et al. IDH1 and IDH2 mutations in gliomas. N Engl J Med 2009; 360: 765–773.

    CAS  Article  Google Scholar 

  3. 3

    Mardis ER, Ding L, Dooling DJ, Larson DE, McLellan MD, Chen K et al. Recurring mutations found by sequencing an acute myeloid leukemia genome. N Engl J Med 2009; 361: 1058–1066.

    CAS  Article  Google Scholar 

  4. 4

    Green A, Beer P . Somatic mutations of IDH1 and IDH2 in the leukemic transformation of myeloproliferative neoplasms. N Engl J Med 2010; 362: 369–370.

    CAS  Article  Google Scholar 

  5. 5

    Thol F, Weissinger EM, Krauter J, Wagner K, Damm F, Wichmann M et al. IDH1 mutations in patients with myelodysplastic syndromes are associated with an unfavorable prognosis. Haematologica 2010; 95: 1668–1674.

    CAS  Article  Google Scholar 

  6. 6

    Amary MF, Bacsi K, Maggiani F, Damato S, Halai D, Berisha F et al. IDH1 and IDH2 mutations are frequent events in central chondrosarcoma and central and periosteal chondromas but not in other mesenchymal tumours. J Pathol 2011; 224: 334–343.

    CAS  Article  Google Scholar 

  7. 7

    Cairns RA, Iqbal J, Lemonnier F, Kucuk C, de Leval L, Jais JP et al. IDH2 mutations are frequent in angioimmunoblastic T-cell lymphoma. Blood 2012; 119: 1901–1903.

    CAS  Article  Google Scholar 

  8. 8

    Shibata T, Kokubu A, Miyamoto M, Sasajima Y, Yamazaki N . Mutant IDH1 confers an in vivo growth in a melanoma cell line with BRAF mutation. Am J Pathol 2011; 178: 1395–1402.

    CAS  Article  Google Scholar 

  9. 9

    Murugan AK, Bojdani E, Xing M . Identification and functional characterization of isocitrate dehydrogenase 1 (IDH1) mutations in thyroid cancer. Biochem Biophys Res Commun 2010; 393: 555–559.

    CAS  Article  Google Scholar 

  10. 10

    Thol F, Damm F, Wagner K, Göhring G, Schlegelberger B, Hölzer D et al. Prognostic impact of IDH2 mutations in cytogenetically normal acute myeloid leukemia. Blood 2010; 116: 614–616.

    CAS  Article  Google Scholar 

  11. 11

    Wagner K, Damm F, Göhring G, Gorlich K, Heuser M, Schäfer I et al. Impact of IDH1 R132 mutations and an IDH1 single nucleotide polymorphism in cytogenetically normal acute myeloid leukemia: SNP rs11554137 is an adverse prognostic factor. J Clin Oncol 2010; 28: 2356–2364.

    CAS  Article  Google Scholar 

  12. 12

    Paschka P, Schlenk RF, Gaidzik VI, Habdank M, Kronke J, Bullinger L et al. 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 2010; 28: 3636–3643.

    CAS  Article  Google Scholar 

  13. 13

    Ward PS, Patel J, Wise DR, Abdel-Wahab O, Bennett BD, Coller HA et al. The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate. Cancer Cell 2010; 17: 225–234.

    CAS  Article  Google Scholar 

  14. 14

    Dang L, White DW, Gross S, Bennett BD, Bittinger MA, Driggers EM et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 2010; 465: 966.

    CAS  Article  Google Scholar 

  15. 15

    Gross S, Cairns RA, Minden MD, Driggers EM, Bittinger MA, Jang HG et al. Cancer-associated metabolite 2-hydroxyglutarate accumulates in acute myelogenous leukemia with isocitrate dehydrogenase 1 and 2 mutations. J Exp Med 2010; 207: 339–344.

    CAS  Article  Google Scholar 

  16. 16

    Sellner L, Capper D, Meyer J, Langhans CD, Hartog CM, Pfeifer H et al. Increased levels of 2-hydroxyglutarate in AML patients with IDH1-R132H and IDH2-R140Q mutations. Eur J Haematol 2010; 85: 457–459.

    Article  Google Scholar 

  17. 17

    Sasaki M, Knobbe CB, Munger JC, Lind EF, Brenner D, Brüstle A et al. IDH1(R132H) mutation increases murine haematopoietic progenitors and alters epigenetics. Nature 2012; 488: 656–659.

    CAS  Article  Google Scholar 

  18. 18

    Lu C, Ward PS, Kapoor GS, Rohle D, Turcan S, Abdel-Wahab O et al. IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature 2012; 483: 474–478.

    CAS  Article  Google Scholar 

  19. 19

    Turcan S, Rohle D, Goenka A, Walsh LA, Fang F, Yilmaz E et al. IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype. Nature 2012; 483: 479–483.

    CAS  Article  Google Scholar 

  20. 20

    Figueroa ME, Abdel-Wahab O, Lu C, Ward PS, Patel J, Shih A et al. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell 2010; 18: 553–567.

    CAS  Article  Google Scholar 

  21. 21

    Losman JA, Looper RE, Koivunen P, Lee S, Schneider RK, McMahon C et al. (R)-2-hydroxyglutarate is sufficient to promote leukemogenesis and its effects are reversible. Science 2013; 339: 1621–1625.

    CAS  Article  Google Scholar 

  22. 22

    Chaturvedi A, Araujo Cruz MM, Jyotsana N, Sharma A, Goparaju R, Schwarzer A et al. Enantiomer-specific and paracrine leukemogenicity of mutant IDH metabolite 2-hydroxyglutarate. Leukemia 2016; 30: 1708–1715.

    CAS  Article  Google Scholar 

  23. 23

    Medeiros BC, Fathi AT, DiNardo CD, Pollyea DA, Chan SM, Swords R . Isocitrate dehydrogenase mutations in myeloid malignancies. Leukemia 2016; 31: 272–281.

    Article  Google Scholar 

  24. 24

    Balss J, Thiede C, Bochtler T, Okun JG, Saadati M, Benner A et al. Pretreatment D-2-hydroxyglutarate serum levels negatively impact on outcome in IDH1-mutated acute myeloid leukemia. Leukemia 2016; 30: 782–788.

    CAS  Article  Google Scholar 

  25. 25

    Wang JH, Chen WL, Li JM, Wu SF, Chen TL, Zhu YM et al. Prognostic significance of 2-hydroxyglutarate levels in acute myeloid leukemia in China. Proc Natl Acad Sci USA 2013; 110: 17017–17022.

    CAS  Article  Google Scholar 

  26. 26

    DiNardo CD, Propert KJ, Loren AW, Paietta E, Sun Z, Levine RL et al. Serum 2-hydroxyglutarate levels predict isocitrate dehydrogenase mutations and clinical outcome in acute myeloid leukemia. Blood 2013; 121: 4917–4924.

    CAS  Article  Google Scholar 

  27. 27

    Wang F, Travins J, DeLaBarre B, Penard-Lacronique V, Schalm S, Hansen E et al. Targeted inhibition of mutant IDH2 in leukemia cells induces cellular differentiation. Science 2013; 340: 622–626.

    CAS  Article  Google Scholar 

  28. 28

    Chaturvedi A, Araujo Cruz MM, Jyotsana N, Sharma A, Yun H, Görlich K et al. Mutant IDH1 promotes leukemogenesis in vivo and can be specifically targeted in human AML. Blood 2013; 122: 2877–2887.

    CAS  Article  Google Scholar 

  29. 29

    Okoye-Okafor UC, Bartholdy B, Cartier J, Gao EN, Pietrak B, Rendina AR et al. New IDH1 mutant inhibitors for treatment of acute myeloid leukemia. Nat Chem Biol 2015; 11: 878–886.

    CAS  Article  Google Scholar 

  30. 30

    DiNardo C, de Botton S, Pollyea DA, Stein EM, Fathi AT, Roboz GJ et al. Molecular profiling and relationship with clinical response in patients with IDH1 mutation-positive hematologic malignancies receiving AG-120, a first-in-class potent inhibitor of mutant IDH1, in addition to data from the completed dose escalation portion of the phase 1 study. Blood 2015; 126: 1306.

    Article  Google Scholar 

  31. 31

    Pusch S, Krausert S, Fischer V, Balss J, Ott M, Schrimpf D et al. Pan-mutant IDH1 inhibitor BAY 1436032 for effective treatment of IDH1 mutant astrocytoma in vivo. Acta Neuropathol 2017; e-pub ahead of print 25 January 2017; doi:10.1007/s00401-017-1677-y.

  32. 32

    Popovici-Muller J, Saunders JO, Salituro FG, Travins JM, Yan S, Zhao F et al. Discovery of the first potent inhibitors of mutant IDH1 that lower tumor 2-HG in vivo. ACS Med Chem Lett 2012; 3: 850–855.

    CAS  Article  Google Scholar 

  33. 33

    Rohle D, Popovici-Muller J, Palaskas N, Turcan S, Grommes C, Campos C et al. An inhibitor of mutant IDH1 delays growth and promotes differentiation of glioma cells. Science 2013; 340: 626–630.

    CAS  Article  Google Scholar 

  34. 34

    Davis M, Pragani R, Popovici-Muller J, Gross S, Thorne N, Salituro F et al. 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: Bethesda, USA, 2010.

    Google Scholar 

  35. 35

    Davis MI, Gross S, Shen M, Straley KS, Pragani R, Lea WA et al. Biochemical, cellular, and biophysical characterization of a potent inhibitor of mutant isocitrate dehydrogenase IDH1. J Biol Chem 2014; 289: 13717–13725.

    CAS  Article  Google Scholar 

  36. 36

    Zheng B, Yao Y, Liu Z, Deng L, Anglin JL, Jiang H et al. Crystallographic investigation and selective inhibition of mutant isocitrate dehydrogenase. ACS Med Chem Lett 2013; 4: 542–546.

    CAS  Article  Google Scholar 

  37. 37

    Birendra KC, DiNardo CD . Evidence for clinical differentiation and differentiation syndrome in patients with acute myeloid leukemia and IDH1 mutations treated with the targeted mutant IDH1 inhibitor, AG-120. Clin Lymphoma Myeloma Leuk 2016; 16: 460–465.

    CAS  Article  Google Scholar 

Download references

Acknowledgements

We acknowledge assistance of the Cell Sorting Core Facility of Hannover Medical School supported in part by the Braukmann–Wittenberg–Herz–Stiftung and the Deutsche Forschungsgemeinschaft. We thank all participating patients and contributing doctors, the staff of the Central Animal Facilities of Hannover Medical School and German Cancer Research Center (DKFZ), and R. Schottmann, K. Görlich, S. Glowotz, M. Wichmann, J. Eisel and S. Schumacher for support. This work was supported by grants from the DKFZ-Bayer Alliance, an ERC grant under the European Union’s Horizon 2020 research and innovation programme (No. 638035), by grants 110284, 110287, 110292 and 111267 from Deutsche Krebshilfe; grant DJCLS R13/14 from the Deutsche José Carreras Leukämie-Stiftung e.V; the German Federal Ministry of Education and Research grant 01EO0802 (IFB-Tx); DFG grants KR1981/4-1, HE5240/5-1 and HE5240/6-1; grants from Wilhelm Sander-Stiftung, Dieter-Schlag Stiftung, a HiLF grant from Hannover Medical School awarded to AC, and a Stiftung für Krebs- und Scharlachforschung Mannheim grant to LH.

Author contributions

AK, MH, AC and LH conceived and designed the study; AC, LH, SP, LK, RG, DS, SK, TB, EAS, AS, AB, RG, MMA-C, FT, RG, AG, ADH, AD, KR, MH and AK collected, analyzed, and assembled the data; OP, KZ, LT, RN, AH, HR, HH-S and MB provided critical reagents; AK and MH wrote the manuscript; and all authors reviewed the data, and edited and approved the final version of the manuscript.

Author information

Affiliations

Authors

Corresponding author

Correspondence to A Krämer.

Ethics declarations

Competing interests

MH received research support from Bayer. The remaining authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on the Leukemia website

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Chaturvedi, A., Herbst, L., Pusch, S. et al. Pan-mutant-IDH1 inhibitor BAY1436032 is highly effective against human IDH1 mutant acute myeloid leukemia in vivo. Leukemia 31, 2020–2028 (2017). https://doi.org/10.1038/leu.2017.46

Download citation

Further reading

Search

Quick links