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.
journal_name
Cancer Resjournal_title
Cancer researchauthors
Picaud S,Fedorov O,Thanasopoulou A,Leonards K,Jones K,Meier J,Olzscha H,Monteiro O,Martin S,Philpott M,Tumber A,Filippakopoulos P,Yapp C,Wells C,Che KH,Bannister A,Robson S,Kumar U,Parr N,Lee K,Lugo D,Jeffrey Pdoi
10.1158/0008-5472.CAN-15-0236subject
Has Abstractpub_date
2015-12-01 00:00:00pages
5106-5119issue
23eissn
0008-5472issn
1538-7445journal_volume
75pub_type
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