> Details

Yen, Katharine; Travins, Jeremy; Wang, Fang; David, Muriel D.; Artin, Erin; Straley, Kimberly; Padyana, Anil; Gross, Stefan; DeLaBarre, Byron; Tobin, Erica; Chen, Yue; Nagaraja, Raj; Choe, Sung; Jin, Lei; Konteatis, Zenon; Cianchetta, Giovanni; Saunders, Jeffrey O.; Salituro, Francesco G.; Quivoron, Cyril; Opolon, Paule; Bawa, Olivia; Saada, Véronique; Paci, Angelo; Broutin, Sophie; [...]

AG-221, a First-in-Class Therapy Targeting Acute Myeloid Leukemia Harboring Oncogenic IDH2 Mutations

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  • Media type: E-Article
  • Title: AG-221, a First-in-Class Therapy Targeting Acute Myeloid Leukemia Harboring Oncogenic IDH2 Mutations
  • Contributor: Yen, Katharine; Travins, Jeremy; Wang, Fang; David, Muriel D.; Artin, Erin; Straley, Kimberly; Padyana, Anil; Gross, Stefan; DeLaBarre, Byron; Tobin, Erica; Chen, Yue; Nagaraja, Raj; Choe, Sung; Jin, Lei; Konteatis, Zenon; Cianchetta, Giovanni; Saunders, Jeffrey O.; Salituro, Francesco G.; Quivoron, Cyril; Opolon, Paule; Bawa, Olivia; Saada, Véronique; Paci, Angelo; Broutin, Sophie; [...]
  • imprint: American Association for Cancer Research (AACR), 2017
  • Published in: Cancer Discovery
  • Language: English
  • DOI: 10.1158/2159-8290.cd-16-1034
  • ISSN: 2159-8274; 2159-8290
  • Origination:
  • Footnote:
  • Description: <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>
  • Access State: Open Access