Rational design, synthesis and biological evaluation of benzo[d]isoxazole derivatives as potent BET bivalent inhibitors for potential treatment of prostate cancer

Multivalency is an attractive strategy for effective binding to target protein. Bromodomain and extra-terminal (BET) family features two tandem bromodomains (BD1, BD2), which are considered to be potential new tar-gets for prostate cancer. Herein, we report the rational design, optimization, and evaluation of a class of novel BET bivalent inhibitors based on our monovalent BET inhibitor 7 (Y06037). The representative bivalent inhibitor 17b effectively inhibited the cell growth of LNCaP, exhibiting 32 folds more potency than monovalent inhibitor 7. Besides, 17b induced 95.1 % PSA regression in LNCaP cell at 2 mu M. Docking study was further carried out to reveal the potential binding mode of 17b with two BET bromodomains. Our study demonstrates that 17b (Y13021) is a promising BET bivalent inhibitor for the treatment of prostate cancer.

Automated summary

In this study, a class of novel BET bivalent inhibitors based on a monovalent BET inhibitor 7 (Y06037) was designed, optimized, and evaluated. The representative bivalent inhibitor 17b exhibited 32-fold greater potency in inhibiting cell growth in LNCaP compared to monovalent inhibitor 7. Furthermore, 17b induced 95.1% PSA regression in LNCaP cells at a concentration of 2 μM. Docking study revealed the potential binding mode of 17b with two BET bromodomains. These findings suggest that 17b (Y13021) is a promising BET bivalent inhibitor for the treatment of prostate cancer.