6VEI
Crystal Structure of Human Cytosolic Isocitrate Dehydrogenase (IDH1) R132H Mutant in Complex with NADPH and AG-881 (Vorasidenib) Inhibitor
Summary for 6VEI
| Entry DOI | 10.2210/pdb6vei/pdb |
| Related | 6VFZ 6VG0 |
| Descriptor | Isocitrate dehydrogenase [NADP] cytoplasmic, NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, SULFATE ION, ... (10 entities in total) |
| Functional Keywords | idh, cytosolic nadp-isocitrate dehydrogenase, oxalosuccinate decarboxylase, nadp(+)-specific icdh, idp, antitumor protein |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 2 |
| Total formula weight | 99585.38 |
| Authors | Padyana, A.,Jin, L. (deposition date: 2020-01-02, release date: 2020-02-05, Last modification date: 2023-10-11) |
| Primary citation | 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 Cited by 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: 32071674DOI: 10.1021/acsmedchemlett.9b00509 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.1 Å) |
Structure validation
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