Rvx-2135 Is A Novel, Orally Bioavailable Epigenetic Bet Inhibitor That Synergizes With Cytarabine And Idarubicin To Inhibit Proliferation Of Acute Myeloid Leukemia Cells.
Cancer Research(2013)
Abstract
Current treatment of acute myeloid leukemia (AML) often includes a combination of intravenous cytarabine (Ara-C) and an anthracycline such as idarubicin. Bromodomain and extra-terminal domain (BET) proteins contain two bromodomains that bind to acetylated lysines in histones and regulate gene transcription by an epigenetic mechanism. Here we describe a novel small molecule BET inhibitor, RVX-2135, which selectively binds recombinant BET bromodomains of BRD2, BRD3, and BRD4 but not non-BET bromodomains. RVX-2135 inhibited BRD2, BRD3, and BRD4 dual bromodomains binding to acetylated histones in vitro with sub to low micromolar IC50 values. In the human AML cell line MV4-11, RVX-2135 displaced BET proteins from chromatin and significantly reduced expression of c-MYC and BCL-2 mRNAs, with IC50s of 4 and 5 μM, respectively. RVX-2135 inhibited proliferation of cultured MV4-11 cells with an IC50 value of 6 μM, and induced cell cycle arrest and apoptosis. In vivo, nude mice bearing MV4-11 xenografts were treated orally with RVX-2135 at doses of 75 and 120 mg/kg b.i.d, and showed tumor growth inhibition of 77 and 92% respectively. There was a corresponding inhibition of c-MYC and BCL-2 mRNA expression in the xenograft tumors. In combination therapy in vitro, RVX-2135 synergized with idarubicin and cytarabine, with Chou-Talalay9s combination indices of 0.17 and 0.18, respectively. The synergistic effect also translated into increased apoptosis when cytarabine was combined with RVX-2135. Similar data were seen with BET inhibitors from different chemical scaffolds, suggesting that this may represent a promising new class of drugs for AML. Citation Format: Eric Campeau, Ravi Jahagirdar, Jin Wu, Emily M. Gesner, Olesya Kharenko, Raymond Yu, Sarah Attwell, Henrik C. Hansen, Gregory S. Wagner, Kevin G. McLure, Peter R. Young. RVX-2135 is a novel, orally bioavailable epigenetic BET inhibitor that synergizes with cytarabine and idarubicin to inhibit proliferation of acute myeloid leukemia cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-92. doi:10.1158/1538-7445.AM2013-LB-92
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Key words
bioavailable epigenetic bet inhibitor,acute myeloid leukemia cells,acute myeloid leukemia,idarubicin
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