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Publication Abstract from PubMed

Through a structure-based irreversible drug design approach, we have discovered a highly potent IDH1-mutant inhibitor compound 16 (IHMT-IDH1-053) (IC(50) = 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 (IC(50) = 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.

Structure-based discovery of IHMT-IDH1-053 as a potent irreversible IDH1 mutant selective inhibitor.,Liang Q, Wang B, Zou F, Guo G, Wang W, Wang W, Liu Q, Shen L, Hu C, Wang W, Wang A, Huang T, He Y, Xia R, Ge J, Liu J, Liu Q Eur J Med Chem. 2023 Aug 5;256:115411. doi: 10.1016/j.ejmech.2023.115411. Epub , 2023 May 12. PMID:37209613^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.