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Acute myeloid leukemia

In vivo efficacy of mutant IDH1 inhibitor HMS-101 and structural resolution of distinct binding site

Leukemia volume 34, pages 416–426 (2020)Cite this article

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Abstract

Mutations in isocitrate dehydrogenase 1 (IDH1) are found in 6% of AML patients. Mutant IDH produces R-2-hydroxyglutarate (R-2HG), which induces histone- and DNA-hypermethylation through the inhibition of epigenetic regulators, thus linking metabolism to tumorigenesis. Here we report the biochemical characterization, in vivo antileukemic effects, structural binding, and molecular mechanism of the inhibitor HMS-101, which inhibits the enzymatic activity of mutant IDH1 (IDH1mut). Treatment of IDH1mut primary AML cells reduced 2-hydroxyglutarate levels (2HG) and induced myeloid differentiation in vitro. Co-crystallization of HMS-101 and mutant IDH1 revealed that HMS-101 binds to the active site of IDH1mut in close proximity to the regulatory segment of the enzyme in contrast to other IDH1 inhibitors. HMS-101 also suppressed 2HG production, induced cellular differentiation and prolonged survival in a syngeneic mutant IDH1 mouse model and a patient-derived human AML xenograft model in vivo. Cells treated with HMS-101 showed a marked upregulation of the differentiation-associated transcription factors CEBPA and PU.1, and a decrease in cell cycle regulator cyclin A2. In addition, the compound attenuated histone hypermethylation. Together, HMS-101 is a unique inhibitor that binds to the active site of IDH1mut directly and is active in IDH1mut preclinical models.

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Acknowledgements

We acknowledge the 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 would like to thank all participating patients and contributing doctors, the staff of the Central Animal Facility of Hannover Medical School, and Silke Glowotz, Nadine Kattre, Girish Rajendraprasad, Roopsee Anand, Martin Wichmann, Petra Baruch, and Claudia Thiel for their support. This work was supported by an ERC grant under the European Union’s Horizon 2020 research and innovation program (No. 638035), by grant 70112697 from Deutsche Krebshilfe; and DFG grants HE 5240/5-1, HE 5240/5-2, HE 5240/6-1, and HE 5240/6-2.

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Author notes

  1. These authors contributed equally: Anuhar Chaturvedi, Ramya Goparaju

  2. These authors contributed equally: Matthias Preller and Michael Heuser

Authors and Affiliations

  1. Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany

    Anuhar Chaturvedi, Ramya Goparaju, Charu Gupta, Michelle Maria Araujo Cruz, Arnold Kloos, Kerstin Goerlich, Renate Schottmann, Basem Othman, Arnold Ganser & Michael Heuser

  2. Institute for Biophysical Chemistry, Hannover Medical School, Hannover and Centre for Structural Systems Biology, Hamburg, Germany

    Julia Weder, Thomas Klünemann & Matthias Preller

  3. Department of Clinical Chemistry, VU University Medical Center, Amsterdam, The Netherlands

    Eduard A. Struys

  4. Research Core Unit Metabolomics, Institute of Pharmacology, Hannover Medical School, Hannover, Germany

    Heike Bähre

  5. Institute of Clinical Chemistry, Hannover Medical School, Hannover, Germany

    Denis Grote-Koska & Korbinian Brand

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  1. Anuhar Chaturvedi
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Contributions

AC, RG, MP, and MH conceived and designed the study. AC, RG, CG, JW,TK, MM, AK, KG, RS, BO, ES, HB, D GK, and KB, collected the data. AC, RG, CG, MP, and MH analyzed and assembled the data. AG and MH collected patient samples and provided the patient data. AC, MP, and MH wrote the manuscript. All authors reviewed the data and edited and approved the final version of the manuscript.

Corresponding authors

Correspondence to Matthias Preller or Michael Heuser.

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Conflict of interest

AC, MP, and MH have filed an EP and US patent application for HMS-101 (based on PCT/EP2014/059898 with priority of 2013). The remaining authors declare that they have no conflict of interest.

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Chaturvedi, A., Goparaju, R., Gupta, C. et al. In vivo efficacy of mutant IDH1 inhibitor HMS-101 and structural resolution of distinct binding site. Leukemia 34, 416–426 (2020). https://doi.org/10.1038/s41375-019-0582-x

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