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

Somatic gain-of-function mutations in isocitrate dehydrogenases (<i>IDH</i>) 1 and 2 are found in multiple hematologic and solid tumors, leading to accumulation of the oncometabolite (<i>R</i>)-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. <i>In vitro</i> 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 <i>IDH2</i> mutation-positive acute myeloid leukemia (AML) cells <i>ex vivo</i> and in xenograft mouse models. AG-221 also provided a statistically significant survival benefit in an aggressive IDH2^R140Q-mutant AML xenograft mouse model. These findings supported initiation of the ongoing clinical trials of AG-221 in patients with <i>IDH2</i> mutation-positive advanced hematologic malignancies.<b>Significance:</b> Mutations in <i>IDH1/2</i> 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. <i>Cancer Discov; 7(5); 478-93. ©2017 AACR.</i><i>See related commentary by Thomas and Majeti, p. 459</i><i>See related article by Shih et al., p. 494</i><i>This article is highlighted in the In This Issue feature, p. 443</i>.