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Publication Abstract from PubMed

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 Kd value of 110nM and blocks bromodomain and acetyl lysine interactions with an IC50 value of 100nM. 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.

Benzoxazinone-containing 3,5-dimethylisoxazole derivatives as BET bromodomain inhibitors for treatment of castration-resistant prostate cancer.,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 Eur J Med Chem. 2018 May 25;152:542-559. doi: 10.1016/j.ejmech.2018.04.034. Epub , 2018 Apr 21. PMID:29758518^[3]

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