As a significant co-activator involved in cell cycle and cell growth, differentiation and development, p300/CBP has shown extraordinary potential target in cancer therapy. Herein we designed new compounds from the lead compound A-485 based on molecular dynamic simulations. A series of new spirocyclic chroman derivatives was prepared, characterized and proven to be a potential treatment of prostate cancer. The most potent compound B16 inhibited the proliferation of enzalutamide-resistant 22Rv1 cells with an IC50 value of 96 nM. Furthermore, compounds B16-P2 displayed favorable overall pharmacokinetic profiles, and better tumor growth inhibition than A-485 in an in vivo xenograft model.
Keywords: HAT inhibitors; antitumor activity; p300/CBP.