i-cbp112

Description: I-CBP112 is a specific and potent acetyl-lysine competitive protein-protein interaction inhibitor that targets the bromodomain-containing transcription factors CREBBP (CBP) and EP300 with IC50 of 0.142 and 0.625 uM, respectively. It significantly enhances acetylation by p300 at the histone H3K18 and H3K23 sites. I-CBP112 stimulated H3K18ac by ca.3-fold, I-CBP112 induced enhances acetylation of these same sites by CBP as well as at H4K5. The EC50’s of activation of I-CBP112 on p300- and CBP-mediated H3K18 acetylation are ca.2 uM. Exposure of human and mouse leukemic cell lines to I-CBP112 resulted in substantially impaired colony formation and induced cellular differentiation without significant cytotoxicity. I-CBP112 significantly reduced the leukemia-initiating potential of MLL-AF9(+) acute myeloid leukemia cells in a dose-dependent manner in vitro and in vivo. Interestingly, I-CBP112 increased the cytotoxic activity of BET bromodomain inhibitor JQ1 as well as doxorubicin. The synergistic effects of I-CBP112 and current standard therapy (doxorubicin) as well as emerging treatment strategies (BET inhibition) provide new opportunities for combinatorial treatment of leukemia and potentially other cancers.

References: Biochemistry. 2016 Jul 12; 55(27):3727-34; Cancer Res. 2015 Dec 1; 75(23):5106-5119.