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Generation of a Selective Small Molecule Inhibitor of the CBP/p300 Bromodomain for Leukemia Therapy

Sarah Picaud, Oleg Fedorov, Angeliki Thanasopoulou, Katharina Leonards, Katherine Jones, Julia Meier, Heidi Olzscha, Octovia Monteiro, Sarah Martin, Martin Philpott, Anthony Tumber, Panagis Filippakopoulos, etc.

Cancer Res. 2015 Dec 1;75(23):5106-5119.

PMID: 26552700

Abstract:

The histone acetyltransferases CBP/p300 are involved in recurrent leukemia-associated chromosomal translocations and are key regulators of cell growth. Therefore, efforts to generate inhibitors of CBP/p300 are of clinical value. We developed a specific and potent acetyl-lysine competitive protein-protein interaction inhibitor, I-CBP112, that targets the CBP/p300 bromodomains. 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. Collectively, we report the development and preclinical evaluation of a novel, potent inhibitor targeting CBP/p300 bromodomains that impairs aberrant self-renewal of leukemic cells. 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.

Chemicals Related in the Paper:

Catalog Number Product Name Structure CAS Number Price
IAR4246393 I-CBP112 I-CBP112 Price
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