6Q6F

Crystal structure of IDH1 R132H in complex with HMS101

6Q6F の概要

• エントリーDOI: 10.2210/pdb6q6f/pdb
• 分子名称: Isocitrate dehydrogenase [NADP] cytoplasmic, (2~{R})-2-[2-[(3~{R})-3-(4-fluorophenyl)pyrrolidin-1-yl]ethyl]-1,4-dimethyl-piperazine (2 entities in total)
• 機能のキーワード: inhibitor, isocitrate dehydrogenase, mutant r132h, cytoplasmic, oxidoreductase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 94013.22

構造登録者

Chaturvedi, A.,Goparaju, R.,Gupta, C.,Kluenemann, T.,Araujo Cruz, M.M.,Kloos, A.,Goerlich, K.,Schottmann, R.,Struys, E.A.,Ganser, A.,Preller, M.,Heuser, M. (登録日: 2018-12-10, 公開日: 2019-10-16, 最終更新日: 2024-01-24)

主引用文献

Chaturvedi, A.,Goparaju, R.,Gupta, C.,Weder, J.,Klunemann, T.,Araujo Cruz, M.M.,Kloos, A.,Goerlich, K.,Schottmann, R.,Othman, B.,Struys, E.A.,Bahre, H.,Grote-Koska, D.,Brand, K.,Ganser, A.,Preller, M.,Heuser, M.
In vivo efficacy of mutant IDH1 inhibitor HMS-101 and structural resolution of distinct binding site.
Leukemia, 34:416-426, 2020

PubMed 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.

PubMed: 31586149
DOI: 10.1038/s41375-019-0582-x

実験手法

X-RAY DIFFRACTION (3.3 Å)