title: AG-221, a First-in-Class Therapy Targeting Acute Myeloid Leukemia Harboring OncogenicIDH2Mutations.
abstract: Somatic gain-of-function mutations in isocitrate dehydrogenases (IDH) 1 and 2 are found in multiple hematologic and solid tumors, leading to accumulation of the oncometabolite (R)-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.In vitrostudies 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 humanIDH2mutation-positive acute myeloid leukemia (AML) cellsex vivoand in xenograft mouse models. AG-221 also provided a statistically significant survival benefit in an aggressive IDH2R140Q-mutant AML xenograft mouse model. These findings supported initiation of the ongoing clinical trials of AG-221 in patients withIDH2mutation-positive advanced hematologic malignancies.Significance:Mutations inIDH1/2are 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.Cancer Discov; 7(5); 478-93. ©2017 AACR.See related commentary by Thomas and Majeti, p. 459See related article by Shih et al., p. 494This article is highlighted in the In This Issue feature, p. 443.
authors.affiliation: Agios Pharmaceuticals, Inc., Cambridge, Massachusetts.
authors.forename: Katharine
authors.initials: K
authors.lastname: Yen
authors.affiliation: Agios Pharmaceuticals, Inc., Cambridge, Massachusetts.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Travins
authors.affiliation: Agios Pharmaceuticals, Inc., Cambridge, Massachusetts.
authors.forename: Fang
authors.initials: F
authors.lastname: Wang
authors.affiliation: INSERM U1170, Villejuif, France.|Gustave Roussy, Université Paris-Saclay, Villejuif, France.|Equipe Labellisée Ligue Contre le Cancer, Villejuif, France.
authors.forename: Muriel D
authors.initials: MD
authors.lastname: David
authors.affiliation: Agios Pharmaceuticals, Inc., Cambridge, Massachusetts.
authors.forename: Erin
authors.initials: E
authors.lastname: Artin
authors.affiliation: Agios Pharmaceuticals, Inc., Cambridge, Massachusetts.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Straley
authors.affiliation: Agios Pharmaceuticals, Inc., Cambridge, Massachusetts.
authors.forename: Anil
authors.initials: A
authors.lastname: Padyana
authors.affiliation: Agios Pharmaceuticals, Inc., Cambridge, Massachusetts.
authors.forename: Stefan
authors.initials: S
authors.lastname: Gross
authors.affiliation: Agios Pharmaceuticals, Inc., Cambridge, Massachusetts.
authors.forename: Byron
authors.initials: B
authors.lastname: DeLaBarre
authors.affiliation: Agios Pharmaceuticals, Inc., Cambridge, Massachusetts.
authors.forename: Erica
authors.initials: E
authors.lastname: Tobin
authors.affiliation: Agios Pharmaceuticals, Inc., Cambridge, Massachusetts.
authors.forename: Yue
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Agios Pharmaceuticals, Inc., Cambridge, Massachusetts.
authors.forename: Raj
authors.initials: R
authors.lastname: Nagaraja
authors.affiliation: Agios Pharmaceuticals, Inc., Cambridge, Massachusetts.
authors.forename: Sung
authors.initials: S
authors.lastname: Choe
authors.affiliation: Agios Pharmaceuticals, Inc., Cambridge, Massachusetts.
authors.forename: Lei
authors.initials: L
authors.lastname: Jin
authors.affiliation: Agios Pharmaceuticals, Inc., Cambridge, Massachusetts.
authors.forename: Zenon
authors.initials: Z
authors.lastname: Konteatis
authors.affiliation: Agios Pharmaceuticals, Inc., Cambridge, Massachusetts.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Cianchetta
authors.affiliation: Agios Pharmaceuticals, Inc., Cambridge, Massachusetts.
authors.forename: Jeffrey O
authors.initials: JO
authors.lastname: Saunders
authors.affiliation: Agios Pharmaceuticals, Inc., Cambridge, Massachusetts.
authors.forename: Francesco G
authors.initials: FG
authors.lastname: Salituro
authors.affiliation: INSERM U1170, Villejuif, France.|Gustave Roussy, Université Paris-Saclay, Villejuif, France.|Equipe Labellisée Ligue Contre le Cancer, Villejuif, France.
authors.forename: Cyril
authors.initials: C
authors.lastname: Quivoron
authors.affiliation: Plateforme d'évaluation préclinique, Gustave Roussy, Université Paris-Saclay, Villejuif, France.
authors.forename: Paule
authors.initials: P
authors.lastname: Opolon
authors.affiliation: Plateforme d'évaluation préclinique, Gustave Roussy, Université Paris-Saclay, Villejuif, France.
authors.forename: Olivia
authors.initials: O
authors.lastname: Bawa
authors.affiliation: INSERM U1170, Villejuif, France.|Gustave Roussy, Université Paris-Saclay, Villejuif, France.|Equipe Labellisée Ligue Contre le Cancer, Villejuif, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Saada
authors.affiliation: Service de Pharmacologie, Département de Biologie et Pathologie Médicales, Gustave Roussy, Université Paris-Saclay, Villejuif, France.
authors.forename: Angelo
authors.initials: A
authors.lastname: Paci
authors.affiliation: Service de Pharmacologie, Département de Biologie et Pathologie Médicales, Gustave Roussy, Université Paris-Saclay, Villejuif, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Broutin
authors.affiliation: INSERM U1170, Villejuif, France.|Gustave Roussy, Université Paris-Saclay, Villejuif, France.|Equipe Labellisée Ligue Contre le Cancer, Villejuif, France.
authors.forename: Olivier A
authors.initials: OA
authors.lastname: Bernard
authors.affiliation: INSERM U1170, Villejuif, France.|Gustave Roussy, Université Paris-Saclay, Villejuif, France.|Equipe Labellisée Ligue Contre le Cancer, Villejuif, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: de Botton
authors.affiliation: Unité de Pathogénie Microbienne Moléculaire, Institut Pasteur, Paris, France.|INSERM U1202, Institut Pasteur, Paris, France.|Laboratoire de Thérapie Cellulaire, Gustave Roussy, Université Paris-Saclay, Villejuif, France.
authors.forename: Benoît S
authors.initials: BS
authors.lastname: Marteyn
authors.affiliation: Department of Pathology, Tufts Medical Center, Boston, Massachusetts.
authors.forename: Monika
authors.initials: M
authors.lastname: Pilichowska
authors.affiliation: ShangPharma, Shanghai, China.
authors.forename: YingXia
authors.initials: Y
authors.lastname: Xu
authors.affiliation: ShangPharma, Shanghai, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Fang
authors.affiliation: Viva Biotech Ltd., Shanghai, China.
authors.forename: Fan
authors.initials: F
authors.lastname: Jiang
authors.affiliation: Viva Biotech Ltd., Shanghai, China.
authors.forename: Wentao
authors.initials: W
authors.lastname: Wei
authors.affiliation: Agios Pharmaceuticals, Inc., Cambridge, Massachusetts.
authors.forename: Shengfang
authors.initials: S
authors.lastname: Jin
authors.affiliation: Agios Pharmaceuticals, Inc., Cambridge, Massachusetts.
authors.forename: Lee
authors.initials: L
authors.lastname: Silverman
authors.affiliation: Agios Pharmaceuticals, Inc., Cambridge, Massachusetts.
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.affiliation: Agios Pharmaceuticals, Inc., Cambridge, Massachusetts.
authors.forename: Hua
authors.initials: H
authors.lastname: Yang
authors.affiliation: Agios Pharmaceuticals, Inc., Cambridge, Massachusetts.
authors.forename: Lenny
authors.initials: L
authors.lastname: Dang
authors.affiliation: Agios Pharmaceuticals, Inc., Cambridge, Massachusetts.
authors.forename: Marion
authors.initials: M
authors.lastname: Dorsch
authors.affiliation: INSERM U1170, Villejuif, France.|Gustave Roussy, Université Paris-Saclay, Villejuif, France.|Equipe Labellisée Ligue Contre le Cancer, Villejuif, France.
authors.forename: Virginie
authors.initials: V
authors.lastname: Penard-Lacronique
authors.affiliation: Agios Pharmaceuticals, Inc., Cambridge, Massachusetts.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Biller
authors.affiliation: Agios Pharmaceuticals, Inc., Cambridge, Massachusetts. Shinsan.Su@agios.com.
authors.forename: Shin-San Michael
authors.initials: SM
authors.lastname: Su
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000037:antagonists & inhibitors* / Q000235:genetics; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D051379:Mice; D009154:Mutation; D014227:Triazines / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000631:Aminopyridines; D000970:Antineoplastic Agents; D014227:Triazines; C000605269:enasidenib; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase