6VG0

CRYSTAL STRUCTURE OF HUMAN CYTOSOLIC ISOCITRATE DEHYDROGENASE (IDH1) R132H MUTANT IN COMPLEX WITH NADPH and AGI-15056

6VG0 の概要

• エントリーDOI: 10.2210/pdb6vg0/pdb
• 関連するPDBエントリー: 6VE1 6VFZ
• 分子名称: Isocitrate dehydrogenase [NADP] cytoplasmic, NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, N~2~,N~4~-bis[(1R)-1-cyclopropylethyl]-6-[6-(trifluoromethyl)pyridin-2-yl]-1,3,5-triazine-2,4-diamine, ... (4 entities in total)
• 機能のキーワード: idh, cytosolic nadp-isocitrate dehydrogenase, oxalosuccinate decarboxylase, nadp(+)-specific icdh, idp, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 147428.16

構造登録者

Padyana, A.,Jin, L. (登録日: 2020-01-07, 公開日: 2020-02-05, 最終更新日: 2023-10-11)

主引用文献

Konteatis, Z.,Artin, E.,Nicolay, B.,Straley, K.,Padyana, A.K.,Jin, L.,Chen, Y.,Narayaraswamy, R.,Tong, S.,Wang, F.,Zhou, D.,Cui, D.,Cai, Z.,Luo, Z.,Fang, C.,Tang, H.,Lv, X.,Nagaraja, R.,Yang, H.,Su, S.M.,Sui, Z.,Dang, L.,Yen, K.,Popovici-Muller, J.,Codega, P.,Campos, C.,Mellinghoff, I.K.,Biller, S.A.
Vorasidenib (AG-881): A First-in-Class, Brain-Penetrant Dual Inhibitor of Mutant IDH1 and 2 for Treatment of Glioma.
Acs Med.Chem.Lett., 11:101-107, 2020

PubMed Abstract: Inhibitors of mutant isocitrate dehydrogenase (mIDH) 1 and 2 cancer-associated enzymes prevent the accumulation of the oncometabolite d-2-hydroxyglutarate (2-HG) and are under clinical investigation for the treatment of several cancers harboring an IDH mutation. Herein, we describe the discovery of vorasidenib (AG-881), a potent, oral, brain-penetrant dual inhibitor of both mIDH1 and mIDH2. X-ray cocrystal structures allowed us to characterize the compound binding site, leading to an understanding of the dual mutant inhibition. Furthermore, vorasidenib penetrates the brain of several preclinical species and inhibits 2-HG production in glioma tissue by >97% in an orthotopic glioma mouse model. Vorasidenib represents a novel dual mIDH1/2 inhibitor and is currently in clinical development for the treatment of low-grade mIDH glioma.

PubMed: 32071674
DOI: 10.1021/acsmedchemlett.9b00509

実験手法

X-RAY DIFFRACTION (2.66 Å)