In Vitro And In Vivo Characterization Of Cpi-267203, A Potent Inhibitor Of Bromodomain-Containing Proteins

The transcription factor c-Myc regulates diverse biological processes including growth, proliferation, differentiation, quiescence, and senescence or apoptosis. c-Myc proto-oncogene overexpression has been implicated in the genesis of many human malignancies. Identification of compounds that selectively and potently inhibit the expression of c-Myc hence could be beneficial for the treatment of these diseases. We and others have recently shown that inhibiting the binding of bromodomain-containing proteins such as Brd4 to their acetylated histone substrates leads to the specific suppression of c-Myc transcription. We report here the characterization of CPI-267203, a potent, selective and competitive inhibitor of BET domain proteins (Brd4 IC50 = 26 nM and CBP IC50 = 6.0 uM). In vitro, this molecule inhibits IL-6 production (EC50 = 11 nM) induced by lipopolysaccharide (LPS) in acute monocytic leukemia cells (THP1) and c-Myc mRNA production (EC50 = 27 nM) in Burkitt lymphoma cells (Raji). c-Myc mRNA and protein levels decline as early as 4hrs after treatment with CPI-267203, leading to cell cycle arrest and apoptosis. In vivo, CPI-267203 has 84% oral bioavailability and a plasma half-life of 1.9 h. In a xenograft model of human acute myelogenous leukemia (MV4:11), CPI-267203 inhibits the production of c-Myc mRNA and protein, inhibits tumor growth, and triggers tumor apoptosis. Reduction of c-Myc protein levels can also be detected in the normal skin of treated animals, suggesting that the level of c-Myc in the skin might be a useful surrogate pharmacodynamic marker to aid clinical trials. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-237. doi:1538-7445.AM2012-LB-237