title: A small molecule inhibitor of mutant IDH2 rescues cardiomyopathy in a D-2-hydroxyglutaric aciduria type II mouse model.
abstract: D-2-hydroxyglutaric aciduria (D2HGA) type II is a rare neurometabolic disorder caused by germline gain-of-function mutations in isocitrate dehydrogenase 2 (IDH2), resulting in accumulation of D-2-hydroxyglutarate (D2HG). Patients exhibit a wide spectrum of symptoms including cardiomyopathy, epilepsy, developmental delay and limited life span. Currently, there are no effective therapeutic interventions. We generated a D2HGA type II mouse model by introducing the Idh2R140Q mutation at the native chromosomal locus. Idh2R140Q mice displayed significantly elevated 2HG levels and recapitulated multiple defects seen in patients. AGI-026, a potent, selective inhibitor of the human IDH2R140Q-mutant enzyme, suppressed 2HG production, rescued cardiomyopathy, and provided a survival benefit in Idh2R140Q mice; treatment withdrawal resulted in deterioration of cardiac function. We observed differential expression of multiple genes and metabolites that are associated with cardiomyopathy, which were largely reversed by AGI-026. These findings demonstrate the potential therapeutic benefit of an IDH2R140Q inhibitor in patients with D2HGA type II.
authors.affiliation: Agios Pharmaceuticals Inc., 88 Sidney Street, Cambridge, MA, 02139-4169, USA.
authors.forename: Fang
authors.initials: F
authors.lastname: Wang
authors.affiliation: Agios Pharmaceuticals Inc., 88 Sidney Street, Cambridge, MA, 02139-4169, USA.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Travins
authors.affiliation: Oncology Business Unit, WuXi AppTec, Shanghai, China.
authors.forename: Zhizhong
authors.initials: Z
authors.lastname: Lin
authors.affiliation: Agios Pharmaceuticals Inc., 88 Sidney Street, Cambridge, MA, 02139-4169, USA.
authors.forename: Yaguang
authors.initials: Y
authors.lastname: Si
authors.affiliation: Agios Pharmaceuticals Inc., 88 Sidney Street, Cambridge, MA, 02139-4169, USA.
authors.forename: Yue
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Agios Pharmaceuticals Inc., 88 Sidney Street, Cambridge, MA, 02139-4169, USA.
authors.forename: Josh
authors.initials: J
authors.lastname: Powe
authors.affiliation: Agios Pharmaceuticals Inc., 88 Sidney Street, Cambridge, MA, 02139-4169, USA.
authors.forename: Stuart
authors.initials: S
authors.lastname: Murray
authors.affiliation: Agios Pharmaceuticals Inc., 88 Sidney Street, Cambridge, MA, 02139-4169, USA.
authors.forename: Dongwei
authors.initials: D
authors.lastname: Zhu
authors.affiliation: Agios Pharmaceuticals Inc., 88 Sidney Street, Cambridge, MA, 02139-4169, USA.
authors.forename: Erin
authors.initials: E
authors.lastname: Artin
authors.affiliation: Agios Pharmaceuticals Inc., 88 Sidney Street, Cambridge, MA, 02139-4169, USA.
authors.forename: Stefan
authors.initials: S
authors.lastname: Gross
authors.affiliation: Agios Pharmaceuticals Inc., 88 Sidney Street, Cambridge, MA, 02139-4169, USA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Santiago
authors.affiliation: Agios Pharmaceuticals Inc., 88 Sidney Street, Cambridge, MA, 02139-4169, USA.
authors.forename: Mya
authors.initials: M
authors.lastname: Steadman
authors.affiliation: Agios Pharmaceuticals Inc., 88 Sidney Street, Cambridge, MA, 02139-4169, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Kernytsky
authors.affiliation: Agios Pharmaceuticals Inc., 88 Sidney Street, Cambridge, MA, 02139-4169, USA.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Straley
authors.affiliation: Oncology Business Unit, WuXi AppTec, Shanghai, China.
authors.forename: Chenming
authors.initials: C
authors.lastname: Lu
authors.affiliation: Metabolic Unit, Department of Clinical Chemistry, VU University Medical Center/ Neuroscience Campus, Amsterdam, The Netherlands.
authors.forename: Ana
authors.initials: A
authors.lastname: Pop
authors.affiliation: Metabolic Unit, Department of Clinical Chemistry, VU University Medical Center/ Neuroscience Campus, Amsterdam, The Netherlands.
authors.forename: Eduard A
authors.initials: EA
authors.lastname: Struys
authors.affiliation: Metabolic Unit, Department of Clinical Chemistry, VU University Medical Center/ Neuroscience Campus, Amsterdam, The Netherlands.
authors.forename: Erwin E W
authors.initials: EE
authors.lastname: Jansen
authors.affiliation: Metabolic Unit, Department of Clinical Chemistry, VU University Medical Center/ Neuroscience Campus, Amsterdam, The Netherlands.
authors.forename: Gajja S
authors.initials: GS
authors.lastname: Salomons
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, INSERM U1170, Villejuif, France.|Institut Gustave Roussy, Villejuif, France.
authors.forename: Muriel D
authors.initials: MD
authors.lastname: David
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, INSERM U1170, Villejuif, France.|Institut Gustave Roussy, Villejuif, France.
authors.forename: Cyril
authors.initials: C
authors.lastname: Quivoron
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, INSERM U1170, Villejuif, France.|Institut Gustave Roussy, Villejuif, France.
authors.forename: Virginie
authors.initials: V
authors.lastname: Penard-Lacronique
authors.affiliation: Regan Pathology/Toxicology Services, Ashland, OH, USA.
authors.forename: Karen S
authors.initials: KS
authors.lastname: Regan
authors.affiliation: Agios Pharmaceuticals Inc., 88 Sidney Street, Cambridge, MA, 02139-4169, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.affiliation: Agios Pharmaceuticals Inc., 88 Sidney Street, Cambridge, MA, 02139-4169, USA.
authors.forename: Lenny
authors.initials: L
authors.lastname: Dang
authors.affiliation: Agios Pharmaceuticals Inc., 88 Sidney Street, Cambridge, MA, 02139-4169, USA.
authors.forename: Hua
authors.initials: H
authors.lastname: Yang
authors.affiliation: Agios Pharmaceuticals Inc., 88 Sidney Street, Cambridge, MA, 02139-4169, USA.
authors.forename: Lee
authors.initials: L
authors.lastname: Silverman
authors.affiliation: Agios Pharmaceuticals Inc., 88 Sidney Street, Cambridge, MA, 02139-4169, USA.
authors.forename: Samuel
authors.initials: S
authors.lastname: Agresta
authors.affiliation: Agios Pharmaceuticals Inc., 88 Sidney Street, Cambridge, MA, 02139-4169, USA.
authors.forename: Marion
authors.initials: M
authors.lastname: Dorsch
authors.affiliation: Agios Pharmaceuticals Inc., 88 Sidney Street, Cambridge, MA, 02139-4169, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Biller
authors.affiliation: Agios Pharmaceuticals Inc., 88 Sidney Street, Cambridge, MA, 02139-4169, USA.
authors.forename: Katharine
authors.initials: K
authors.lastname: Yen
authors.affiliation: Oncology Business Unit, WuXi AppTec, Shanghai, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Cang
authors.affiliation: Agios Pharmaceuticals Inc., 88 Sidney Street, Cambridge, MA, 02139-4169, USA.
authors.forename: Shin-San Michael
authors.initials: SM
authors.lastname: Su
authors.affiliation: Agios Pharmaceuticals Inc., 88 Sidney Street, Cambridge, MA, 02139-4169, USA. shengfang.jin@agios.com.
authors.forename: Shengfang
authors.initials: S
authors.lastname: Jin
mesh_terms: D000818:Animals; D020739:Brain Diseases, Metabolic, Inborn / Q000188:drug therapy* / Q000235:genetics; D009202:Cardiomyopathies / Q000188:drug therapy*; D004195:Disease Models, Animal; D007521:Isocitrate Dehydrogenase / Q000037:antagonists & inhibitors* / Q000235:genetics; D051379:Mice; D009154:Mutation / Q000187:drug effects* / Q000235:genetics; D054852:Small Molecule Libraries / Q000494:pharmacology*
chemical_list: D054852:Small Molecule Libraries; D007521:Isocitrate Dehydrogenase; C000599591:isocitrate dehydrogenase 2, mouse