Structure-based discovery of IHMT-IDH1-053 as a potent irreversible IDH1 mutant selective inhibitor

  • Eur J Med Chem. 2023 Aug 5;256:115411. doi: 10.1016/j.ejmech.2023.115411.
Qianmao Liang  1 ,  Beilei Wang  2 ,  Fengming Zou  2 ,  Gongrui Guo  3 ,  Wenliang Wang  4 ,  Wei Wang  5 ,  Qingwang Liu  2 ,  Lijuan Shen  1 ,  Chen Hu  2 ,  Wenchao Wang  2 ,  Aoli Wang  2 ,  Tao Huang  3 ,  Yuying He  3 ,  Ruixiang Xia  6 ,  Jian Ge  7 ,  Jing Liu  8 ,  Qingsong Liu  9
Affiliations
  • 1. Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, 230031, PR China; University of Science and Technology of China, Hefei, Anhui, 230026, PR China.
  • 2. Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, 230031, PR China; Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, Anhui, 230031, PR China.
  • 3. Precision Medicine Research Laboratory of Anhui Province, Hefei, Anhui, 230088, PR China.
  • 4. Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, 230031, PR China.
  • 5. Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, 230031, PR China; Precision Medicine Research Laboratory of Anhui Province, Hefei, Anhui, 230088, PR China.
  • 6. Department of Hematology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230022, PR China.
  • 7. Department of Hematology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230022, PR China. Electronic address: [email protected].
  • 8. Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, 230031, PR China; University of Science and Technology of China, Hefei, Anhui, 230026, PR China; Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, Anhui, 230031, PR China. Electronic address: [email protected].
  • 9. Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, 230031, PR China; University of Science and Technology of China, Hefei, Anhui, 230026, PR China; Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, Anhui, 230031, PR China; Precision Medicine Research Laboratory of Anhui Province, Hefei, Anhui, 230088, PR China. Electronic address: [email protected].
PMID: 37209613 DOI: 10.1016/j.ejmech.2023.115411
Abstract

Through a structure-based irreversible drug design approach, we have discovered a highly potent IDH1-mutant inhibitor compound 16 (IHMT-IDH1-053) (IC50 = 4.7 nM), which displays high selectivity against IDH1 mutants over IDH1 wt and IDH2 wt/mutants. The crystal structure demonstrates that 16 binds to the IDH1 R132H protein in the allosteric pocket adjacent to the NAPDH binding pocket through a covalent bond with residue Cys269. 16 inhibits 2-hydroxyglutarate (2-HG) production in IDH1 R132H mutant transfected 293T cells (IC50 = 28 nM). In addition, it inhibits the proliferation of HT1080 cell line and primary AML cells which both bear IDH1 R132 mutants. In vivo, 16 inhibits 2-HG level in a HT1080 xenograft mouse model. Our study suggested that 16 would be a new pharmacological tool to study IDH1 mutant-related pathology and the covalent binding mode provided a novel approach for designing irreversible IDH1 inhibitors.

Keywords
IDH1; Irreversible inhibitor; mIDH1 inhibitor.
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