Discovery of AG-120 (Ivosidenib): A First-in-Class Mutant IDH1 Inhibitor for the Treatment of IDH1 Mutant Cancers.

Autor:	Popovici-Muller J; Agios Pharmaceuticals Inc., Cambridge, Massachusetts 02139, United States., Lemieux RM; Agios Pharmaceuticals Inc., Cambridge, Massachusetts 02139, United States., Artin E; Agios Pharmaceuticals Inc., Cambridge, Massachusetts 02139, United States., Saunders JO; Agios Pharmaceuticals Inc., Cambridge, Massachusetts 02139, United States., Salituro FG; Agios Pharmaceuticals Inc., Cambridge, Massachusetts 02139, United States., Travins J; Agios Pharmaceuticals Inc., Cambridge, Massachusetts 02139, United States., Cianchetta G; Agios Pharmaceuticals Inc., Cambridge, Massachusetts 02139, United States., Cai Z; PharmaResources, Shanghai 201201, China., Zhou D; PharmaResources, Shanghai 201201, China., Cui D; PharmaResources, Shanghai 201201, China., Chen P; PharmaResources, Shanghai 201201, China., Straley K; Agios Pharmaceuticals Inc., Cambridge, Massachusetts 02139, United States., Tobin E; Agios Pharmaceuticals Inc., Cambridge, Massachusetts 02139, United States., Wang F; Agios Pharmaceuticals Inc., Cambridge, Massachusetts 02139, United States., David MD; INSERM U1170 and Gustave Roussy, Villejuif 94800, France., Penard-Lacronique V; INSERM U1170 and Gustave Roussy, Villejuif 94800, France., Quivoron C; INSERM U1170 and Gustave Roussy, Villejuif 94800, France., Saada V; INSERM U1170 and Gustave Roussy, Villejuif 94800, France., de Botton S; INSERM U1170 and Gustave Roussy, Villejuif 94800, France., Gross S; Agios Pharmaceuticals Inc., Cambridge, Massachusetts 02139, United States., Dang L; Agios Pharmaceuticals Inc., Cambridge, Massachusetts 02139, United States., Yang H; Agios Pharmaceuticals Inc., Cambridge, Massachusetts 02139, United States., Utley L; Agios Pharmaceuticals Inc., Cambridge, Massachusetts 02139, United States., Chen Y; Agios Pharmaceuticals Inc., Cambridge, Massachusetts 02139, United States., Kim H; Agios Pharmaceuticals Inc., Cambridge, Massachusetts 02139, United States., Jin S; Agios Pharmaceuticals Inc., Cambridge, Massachusetts 02139, United States., Gu Z; ChemPartner, Shanghai 201203, China., Yao G; ChemPartner, Shanghai 201203, China., Luo Z; ChemPartner, Shanghai 201203, China., Lv X; ChemPartner, Shanghai 201203, China., Fang C; ChemPartner, Shanghai 201203, China., Yan L; ChemPartner, Shanghai 201203, China., Olaharski A; Agios Pharmaceuticals Inc., Cambridge, Massachusetts 02139, United States., Silverman L; Agios Pharmaceuticals Inc., Cambridge, Massachusetts 02139, United States., Biller S; Agios Pharmaceuticals Inc., Cambridge, Massachusetts 02139, United States., Su SM; Agios Pharmaceuticals Inc., Cambridge, Massachusetts 02139, United States., Yen K; Agios Pharmaceuticals Inc., Cambridge, Massachusetts 02139, United States.
Jazyk:	angličtina
Zdroj:	ACS medicinal chemistry letters [ACS Med Chem Lett] 2018 Jan 19; Vol. 9 (4), pp. 300-305. Date of Electronic Publication: 2018 Jan 19 (Print Publication: 2018).
DOI:	10.1021/acsmedchemlett.7b00421
Abstrakt:	Somatic point mutations at a key arginine residue (R132) within the active site of the metabolic enzyme isocitrate dehydrogenase 1 (IDH1) confer a novel gain of function in cancer cells, resulting in the production of d-2-hydroxyglutarate (2-HG), an oncometabolite. Elevated 2-HG levels are implicated in epigenetic alterations and impaired cellular differentiation. IDH1 mutations have been described in an array of hematologic malignancies and solid tumors. Here, we report the discovery of AG-120 (ivosidenib), an inhibitor of the IDH1 mutant enzyme that exhibits profound 2-HG lowering in tumor models and the ability to effect differentiation of primary patient AML samples ex vivo. Preliminary data from phase 1 clinical trials enrolling patients with cancers harboring an IDH1 mutation indicate that AG-120 has an acceptable safety profile and clinical activity. Competing Interests: The authors declare the following competing financial interest(s): S.d.B. serves on advisory boards for Agios and Celgene. S.S.M.S is a consultant for Agios.
Databáze:	MEDLINE
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