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

作者：Picaud Sarah; Fedorov Oleg; Thanasopoulou Angeliki; Leonards Katharina; Jones Katherine; Meier Julia; Olzscha Heidi; Monteiro Octovia; Martin Sarah; Philpott Martin; Tumber Anthony; Filippakopoulos Panagis; Yapp Clarence; Wells Christopher; Che Ka Hing; Bannister Andrew; Robson Samuel; Kumar Umesh; Parr Nigel; Lee Kevin; Lugo Dave; Jeffrey Philip; Taylor Simon; Vecellio Matteo L; Bountra Chas; Brennan Paul E; O'Mahony Alison; Velichko Sharlene; Mueller Susanne

来源：Cancer Research, 2015, 75(23): 5106-5119.

DOI：10.1158/0008-5472.CAN-15-0236

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.

• 出版日期2015-12-1