5I96

Crystal Structure of Human Mitochondrial Isocitrate Dehydrogenase (IDH2) R140Q Mutant Homodimer in Complex with AG-221 (Enasidenib) Inhibitor.

Summary for 5I96

• Entry DOI: 10.2210/pdb5i96/pdb
• Related: 5I95
• Descriptor: Isocitrate dehydrogenase [NADP], mitochondrial, CALCIUM ION, GLYCEROL, ... (8 entities in total)
• Functional Keywords: idh, idh2, enasidenib, ag-221, idh2 ag-221, icd-m, idp nadp(+)-specific icdh oxalosuccinate decarboxylase, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Mitochondrion: P48735
• Total number of polymer chains: 2
• Total formula weight: 106234.93

Authors

Wei, W.,Zhang, B.,Jin, L.,Jiang, F.,DeLaBarre, B.,Travins, J.A.,Padyana, A.K. (deposition date: 2016-02-19, release date: 2017-03-08, Last modification date: 2023-09-27)

Primary citation

Yen, K.,Travins, J.,Wang, F.,David, M.D.,Artin, E.,Straley, K.,Padyana, A.,Gross, S.,DeLaBarre, B.,Tobin, E.,Chen, Y.,Nagaraja, R.,Choe, S.,Jin, L.,Konteatis, Z.,Cianchetta, G.,Saunders, J.O.,Salituro, F.G.,Quivoron, C.,Opolon, P.,Bawa, O.,Saada, V.,Paci, A.,Broutin, S.,Bernard, O.A.,de Botton, S.,Marteyn, B.S.,Pilichowska, M.,Xu, Y.,Fang, C.,Jiang, F.,Wei, W.,Jin, S.,Silverman, L.,Liu, W.,Yang, H.,Dang, L.,Dorsch, M.,Penard-Lacronique, V.,Biller, S.A.,Su, S.M.
AG-221, a First-in-Class Therapy Targeting Acute Myeloid Leukemia Harboring Oncogenic IDH2 Mutations.
Cancer Discov, 7:478-493, 2017

PubMed Abstract: Somatic gain-of-function mutations in isocitrate dehydrogenases () 1 and 2 are found in multiple hematologic and solid tumors, leading to accumulation of the oncometabolite ()-2-hydroxyglutarate (2HG). 2HG competitively inhibits α-ketoglutarate-dependent dioxygenases, including histone demethylases and methylcytosine dioxygenases of the TET family, causing epigenetic dysregulation and a block in cellular differentiation. studies have provided proof of concept for mutant IDH inhibition as a therapeutic approach. We report the discovery and characterization of AG-221, an orally available, selective, potent inhibitor of the mutant IDH2 enzyme. AG-221 suppressed 2HG production and induced cellular differentiation in primary human mutation-positive acute myeloid leukemia (AML) cells and in xenograft mouse models. AG-221 also provided a statistically significant survival benefit in an aggressive IDH2-mutant AML xenograft mouse model. These findings supported initiation of the ongoing clinical trials of AG-221 in patients with mutation-positive advanced hematologic malignancies. Mutations in are identified in approximately 20% of patients with AML and contribute to leukemia via a block in hematopoietic cell differentiation. We have shown that the targeted inhibitor AG-221 suppresses the mutant IDH2 enzyme in multiple preclinical models and induces differentiation of malignant blasts, supporting its clinical development. .

PubMed: 28193778
DOI: 10.1158/2159-8290.CD-16-1034

Experimental method

X-RAY DIFFRACTION (1.55 Å)