251. Benzoxazinone-containing 3,5-dimethylisoxazole derivatives as BET bromodomain inhibitors for treatment of castration-resistant prostate cancer.
- Author
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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, and Xu Y
- Subjects
- Animals, Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Benzoxazines chemistry, Cell Movement drug effects, Cell Proliferation drug effects, Cell Survival drug effects, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Humans, Isoxazoles chemistry, Male, Molecular Structure, Prostatic Neoplasms, Castration-Resistant metabolism, Prostatic Neoplasms, Castration-Resistant pathology, Proteins metabolism, Rats, Rats, Sprague-Dawley, Structure-Activity Relationship, Tumor Cells, Cultured, Antineoplastic Agents pharmacology, Benzoxazines pharmacology, Isoxazoles pharmacology, Prostatic Neoplasms, Castration-Resistant drug therapy, Proteins antagonists & inhibitors
- 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
d value of 110 nM and blocks bromodomain and acetyl lysine interactions with an IC50 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., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)- Published
- 2018
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