AG-221, a First-in-Class Therapy Targeting Acute Myeloid Leukemia Harboring Oncogenic <i>IDH2</i> Mutations
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- Katharine Yen
- 1Agios Pharmaceuticals, Inc., Cambridge, Massachusetts.
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- Jeremy Travins
- 1Agios Pharmaceuticals, Inc., Cambridge, Massachusetts.
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- Fang Wang
- 1Agios Pharmaceuticals, Inc., Cambridge, Massachusetts.
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- Muriel D. David
- 2INSERM U1170, Villejuif, France.
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- Erin Artin
- 1Agios Pharmaceuticals, Inc., Cambridge, Massachusetts.
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- Kimberly Straley
- 1Agios Pharmaceuticals, Inc., Cambridge, Massachusetts.
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- Anil Padyana
- 1Agios Pharmaceuticals, Inc., Cambridge, Massachusetts.
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- Stefan Gross
- 1Agios Pharmaceuticals, Inc., Cambridge, Massachusetts.
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- Byron DeLaBarre
- 1Agios Pharmaceuticals, Inc., Cambridge, Massachusetts.
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- Erica Tobin
- 1Agios Pharmaceuticals, Inc., Cambridge, Massachusetts.
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- Yue Chen
- 1Agios Pharmaceuticals, Inc., Cambridge, Massachusetts.
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- Raj Nagaraja
- 1Agios Pharmaceuticals, Inc., Cambridge, Massachusetts.
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- Sung Choe
- 1Agios Pharmaceuticals, Inc., Cambridge, Massachusetts.
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- Lei Jin
- 1Agios Pharmaceuticals, Inc., Cambridge, Massachusetts.
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- Zenon Konteatis
- 1Agios Pharmaceuticals, Inc., Cambridge, Massachusetts.
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- Giovanni Cianchetta
- 1Agios Pharmaceuticals, Inc., Cambridge, Massachusetts.
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- Jeffrey O. Saunders
- 1Agios Pharmaceuticals, Inc., Cambridge, Massachusetts.
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- Francesco G. Salituro
- 1Agios Pharmaceuticals, Inc., Cambridge, Massachusetts.
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- Cyril Quivoron
- 2INSERM U1170, Villejuif, France.
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- Paule Opolon
- 5Plateforme d'évaluation préclinique, Gustave Roussy, Université Paris-Saclay, Villejuif, France.
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- Olivia Bawa
- 5Plateforme d'évaluation préclinique, Gustave Roussy, Université Paris-Saclay, Villejuif, France.
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- Véronique Saada
- 2INSERM U1170, Villejuif, France.
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- Angelo Paci
- 6Service de Pharmacologie, Département de Biologie et Pathologie Médicales, Gustave Roussy, Université Paris-Saclay, Villejuif, France.
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- Sophie Broutin
- 6Service de Pharmacologie, Département de Biologie et Pathologie Médicales, Gustave Roussy, Université Paris-Saclay, Villejuif, France.
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- Olivier A. Bernard
- 2INSERM U1170, Villejuif, France.
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- Stéphane de Botton
- 2INSERM U1170, Villejuif, France.
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- Benoît S. Marteyn
- 7Unité de Pathogénie Microbienne Moléculaire, Institut Pasteur, Paris, France.
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- Monika Pilichowska
- 10Department of Pathology, Tufts Medical Center, Boston, Massachusetts.
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- YingXia Xu
- 11ShangPharma, Shanghai, China.
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- Cheng Fang
- 11ShangPharma, Shanghai, China.
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- Fan Jiang
- 12Viva Biotech Ltd., Shanghai, China.
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- Wentao Wei
- 12Viva Biotech Ltd., Shanghai, China.
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- Shengfang Jin
- 1Agios Pharmaceuticals, Inc., Cambridge, Massachusetts.
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- Lee Silverman
- 1Agios Pharmaceuticals, Inc., Cambridge, Massachusetts.
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- Wei Liu
- 1Agios Pharmaceuticals, Inc., Cambridge, Massachusetts.
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- Hua Yang
- 1Agios Pharmaceuticals, Inc., Cambridge, Massachusetts.
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- Lenny Dang
- 1Agios Pharmaceuticals, Inc., Cambridge, Massachusetts.
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- Marion Dorsch
- 1Agios Pharmaceuticals, Inc., Cambridge, Massachusetts.
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- Virginie Penard-Lacronique
- 2INSERM U1170, Villejuif, France.
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- Scott A. Biller
- 1Agios Pharmaceuticals, Inc., Cambridge, Massachusetts.
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- Shin-San Michael Su
- 1Agios Pharmaceuticals, Inc., Cambridge, Massachusetts.
説明
<jats:title>Abstract</jats:title> <jats:p>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 vitro 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 IDH2 mutation–positive acute myeloid leukemia (AML) cells ex vivo and 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 with IDH2 mutation–positive advanced hematologic malignancies.</jats:p> <jats:p>Significance: Mutations in IDH1/2 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. Cancer Discov; 7(5); 478–93. ©2017 AACR.</jats:p> <jats:p>See related commentary by Thomas and Majeti, p. 459.</jats:p> <jats:p>See related article by Shih et al., p. 494.</jats:p> <jats:p>This article is highlighted in the In This Issue feature, p. 443</jats:p>
収録刊行物
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- Cancer Discovery
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Cancer Discovery 7 (5), 478-493, 2017-04-30
American Association for Cancer Research (AACR)