Generation of a selective small molecule inhibitor of the CBP/p300 bromodomain for leukemia therapy

S. Picaud, O. Fedorov, A. Thanasopoulou, K. Leonards, K. Jones, J. Meier, H. Olzscha, O. Monteiro, S. Martin, M. Philpott, A. Tumber, P. Filippakopoulos, C. Yapp, C. Wells, Ka Hing Che, Andrew J. Bannister, S. Robson, U. Kumar, N. Parr, H. K. LeeD. Lugo, P. Jeffrey, Rod S. Taylor, M. L. Vecellio, C. Bountra, P. E. Brennan, A. O'Mahony, S. Velichko, S. Muller, D. Hay, D. L. Daniels, M. Urh, N. B. La Thangue, Tony Kouzarides, Rab K. Prinjha, J. Schwaller, S. Knapp

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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.
Original languageEnglish
Pages (from-to)5106-5119
Number of pages14
JournalCancer Research
Volume75
Issue number23
Early online date9 Nov 2015
DOIs
Publication statusPublished - 1 Dec 2015
Externally publishedYes

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