Vorasidenib (AG-881): A first-in-class, brain-penetrant dual inhibitor of mutant IDH1 and 2 for treatment of glioma Research Letter

   

Authors:	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. S. M.; Sui, Z.; Dang, L.; Yen, K.; Popovici-Muller, J.; Codega, P.; Campos, C.; Mellinghoff, I. K.; Biller, S. A.
Title:	Vorasidenib (AG-881): A first-in-class, brain-penetrant dual inhibitor of mutant IDH1 and 2 for treatment of glioma
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.
Keywords:	mutations; isocitrate dehydrogenase; genomic analysis; 2-hydroxyglutarate; vorasidenib; mutant idh1/midh2; ag-881
Journal Title:	ACS Medicinal Chemistry Letters
Volume:	11
Issue:	2
ISSN:	1948-5875
Publisher:	American Chemical Society
Date Published:	2020-02-13
Start Page:	101
End Page:	107
Language:	English
ACCESSION:	WOS:000514222900002
DOI:	10.1021/acsmedchemlett.9b00509
PROVIDER:	wos
PMCID:	PMC7025383
PUBMED:	32071674
Notes:	Article -- Source: Wos

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