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

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

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: gejian@ahmu.edu.cn.
  • 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: jingliu@hmfl.ac.cn.
  • 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: qsliu97@hmfl.ac.cn.
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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