8HB9

Crystal Structure of Human IDH1 R132H Mutant in Complex with NADPH and Compound IHMT-IDH1-053

This is a non-PDB format compatible entry.

Summary for 8HB9

• Entry DOI: 10.2210/pdb8hb9/pdb
• Descriptor: Isocitrate dehydrogenase [NADP] cytoplasmic, [2-[2-[[1-[4-[(1S)-1-[[5-fluoranyl-4-[(4S)-2-oxidanylidene-4-propan-2-yl-1,3-oxazolidin-3-yl]pyrimidin-2-yl]amino]ethyl]phenyl]piperidin-4-yl]sulfamoyl]ethylsulfanylmethyl]-3-oxidanylidene-propyl]-trimethyl-azanium, NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, ... (6 entities in total)
• Functional Keywords: oxidoreductase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 4
• Total formula weight: 193741.26

Authors

Guo, G.,Wang, B.,Liu, J.,Liu, Q. (deposition date: 2022-10-27, release date: 2023-05-24, Last modification date: 2024-11-06)

Primary citation

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.
Structure-based discovery of IHMT-IDH1-053 as a potent irreversible IDH1 mutant selective inhibitor.
Eur.J.Med.Chem., 256:115411-115411, 2023

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

PubMed: 37209613
DOI: 10.1016/j.ejmech.2023.115411

Experimental method

X-RAY DIFFRACTION (2.8 Å)