6C7Q

BRD4 BD2 in complex with compound CE277

Summary for 6C7Q

• Entry DOI: 10.2210/pdb6c7q/pdb
• Descriptor: Bromodomain-containing protein 4, 7-(3,5-dimethyl-1,2-oxazol-4-yl)-6-methoxy-2-methyl-N-(1-methyl-1H-indazol-3-yl)-9H-pyrimido[4,5-b]indol-4-amine (3 entities in total)
• Functional Keywords: bromodomain, transcription, transcription-transcription inhibitor complex, transcription/transcription inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 15720.05

Authors

Meagher, J.L.,Stuckey, J.A. (deposition date: 2018-01-23, release date: 2018-08-01, Last modification date: 2024-10-16)

Primary citation

Zhao, Y.,Zhou, B.,Bai, L.,Liu, L.,Yang, C.Y.,Meagher, J.L.,Stuckey, J.A.,McEachern, D.,Przybranowski, S.,Wang, M.,Ran, X.,Aguilar, A.,Hu, Y.,Kampf, J.W.,Li, X.,Zhao, T.,Li, S.,Wen, B.,Sun, D.,Wang, S.
Structure-Based Discovery of CF53 as a Potent and Orally Bioavailable Bromodomain and Extra-Terminal (BET) Bromodomain Inhibitor.
J. Med. Chem., 61:6110-6120, 2018

PubMed Abstract: We report the structure-based discovery of CF53 (28) as a highly potent and orally active inhibitor of bromodomain and extra-terminal (BET) proteins. By the incorporation of a NH-pyrazole group into the 9H-pyrimido[4,5- b]indole core, we identified a series of compounds that bind to BRD4 BD1 protein with K values of <1 nM and achieve low nanomolar potencies in the cell growth inhibition of leukemia and breast cancer cells. The most-promising compound, CF53, possesses excellent oral pharmacokinetic properties and achieves significant antitumor activity in both triple-negative breast cancer and acute leukemia xenograft models in mice. Determination of the co-crystal structure of CF53 with the BRD4 BD1 protein provides a structural basis for its high binding affinity to BET proteins. CF53 is very selective over non-BET bromodomain-containing proteins. These data establish CF53 as a potent, selective, and orally active BET inhibitor, which warrants further evaluation for advanced preclinical development.

PubMed: 30015487
DOI: 10.1021/acs.jmedchem.8b00483

Experimental method

X-RAY DIFFRACTION (1.51 Å)