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Publication Abstract from PubMed

We have designed and synthesized 9H-pyrimido[4,5-b]indole-containing compounds to obtain potent and orally bioavailable BET inhibitors. By incorporation of an indole or a quinoline moiety to the 9H-pyrimido[4,5-b]indole core, we identified a series of small molecules showing high binding affinities to BET proteins and low nanomolar potencies in inhibition of cell growth in acute leukemia cell lines. One such compound, 4-(6-methoxy-2-methyl-4-(quinolin-4-yl)-9H-pyrimido[4,5-b]indol-7-yl)-3,5-dimethy lisoxazole (31) has excellent microsomal stability and good oral pharmacokinetics in rats and mice. Orally administered, 31 achieves significant antitumor activity in the MV4;11 leukemia and MDA-MB-231 triple-negative breast cancer xenograft models in mice. Determination of the cocrystal structure of 31 with BRD4 BD2 provides a structural basis for its high binding affinity to BET proteins. Testing its binding affinities against other bromodomain-containing proteins shows that 31 is a highly selective inhibitor of BET proteins. Our data show that 31 is a potent, selective, and orally active BET inhibitor.

Structure-Based Discovery of 4-(6-Methoxy-2-methyl-4-(quinolin-4-yl)-9H-pyrimido[4,5-b]indol-7-yl)-3,5-dimethy lisoxazole (CD161) as a Potent and Orally Bioavailable BET Bromodomain Inhibitor.,Zhao Y, Bai L, Liu L, McEachern D, Stuckey JA, Meagher JL, Yang CY, Ran X, Zhou B, Hu Y, Li X, Wen B, Zhao T, Li S, Sun D, Wang S J Med Chem. 2017 May 11;60(9):3887-3901. doi: 10.1021/acs.jmedchem.7b00193. Epub , 2017 May 2. PMID:28463487^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.