5UOO

BRD4 bromodomain 2 in complex with CD161

Summary for 5UOO

• Entry DOI: 10.2210/pdb5uoo/pdb
• Descriptor: Bromodomain-containing protein 4, 7-(3,5-dimethyl-1,2-oxazol-4-yl)-6-methoxy-2-methyl-4-(quinolin-4-yl)-9H-pyrimido[4,5-b]indole (3 entities in total)
• Functional Keywords: bromodomain, transcription
• Biological source: Homo sapiens (Human)
• Cellular location: Nucleus: O60885
• Total number of polymer chains: 1
• Total formula weight: 15702.03

Authors

Meagher, J.L.,Stuckey, J.A. (deposition date: 2017-02-01, release date: 2017-05-17, Last modification date: 2024-11-06)

Primary citation

Zhao, Y.,Bai, L.,Liu, L.,McEachern, D.,Stuckey, J.A.,Meagher, J.L.,Yang, C.Y.,Ran, X.,Zhou, B.,Hu, Y.,Li, X.,Wen, B.,Zhao, T.,Li, S.,Sun, D.,Wang, S.
Structure-Based Discovery of 4-(6-Methoxy-2-methyl-4-(quinolin-4-yl)-9H-pyrimido[4,5-b]indol-7-yl)-3,5-dimethylisoxazole (CD161) as a Potent and Orally Bioavailable BET Bromodomain Inhibitor.
J. Med. Chem., 60:3887-3901, 2017

PubMed Abstract: 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-dimethylisoxazole (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.

PubMed: 28463487
DOI: 10.1021/acs.jmedchem.7b00193

Experimental method

X-RAY DIFFRACTION (1.69 Å)