5YQX

Crystal Structure Analysis of the BRD4

Summary for 5YQX

• Entry DOI: 10.2210/pdb5yqx/pdb
• Descriptor: Bromodomain-containing protein 4, (2R)-2-(cyclopropylmethyl)-7-(3,5-dimethyl-1,2-oxazol-4-yl)-4H-1,4-benzoxazin-3-one, 1,2-ETHANEDIOL, ... (5 entities in total)
• Functional Keywords: bet, brd4, bromodomain, transcription
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 17090.71

Authors

Xue, X.,Zhang, Y.,Wang, C.,Song, M. (deposition date: 2017-11-08, release date: 2018-11-28, Last modification date: 2024-03-27)

Primary citation

Xue, X.,Zhang, Y.,Wang, C.,Zhang, M.,Xiang, Q.,Wang, J.,Wang, A.,Li, C.,Zhang, C.,Zou, L.,Wang, R.,Wu, S.,Lu, Y.,Chen, H.,Ding, K.,Li, G.,Xu, Y.
Benzoxazinone-containing 3,5-dimethylisoxazole derivatives as BET bromodomain inhibitors for treatment of castration-resistant prostate cancer.
Eur.J.Med.Chem., 152:542-559, 2018

PubMed Abstract: The bromodomain and extra-terminal proteins (BET) have emerged as promising therapeutic targets for the treatment of castration-resistant prostate cancer (CRPC). We report the design, synthesis and evaluation of a new series of benzoxazinone-containing 3,5-dimethylisoxazole derivatives as selective BET inhibitors. One of the new compounds, (R)-12 (Y02234), binds to BRD4(1) with a K value of 110 nM and blocks bromodomain and acetyl lysine interactions with an IC value of 100 nM. It also exhibits selectivity for BET over non-BET bromodomain proteins and demonstrates reasonable anti-proliferation and colony formation inhibition effect in prostate cancer cell lines such as 22Rv1 and C4-2B. The BRD4 inhibitor (R)-12 also significantly suppresses the expression of ERG, Myc and AR target gene PSA at the mRNA level in prostate cancer cells. Treatment with (R)-12 significantly suppresses the tumor growth of prostate cancer (TGI = 70%) in a 22Rv1-derived xenograft model. These data suggest that compound (R)-12 is a promising lead compound for the development of a new class of therapeutics for the treatment of CRPC.

PubMed: 29758518
DOI: 10.1016/j.ejmech.2018.04.034

Experimental method

X-RAY DIFFRACTION (1.82 Å)