Anticancer Inhibitors of AR-Mediated Gene Expression

摘要

New drugs that halt the progression of prostate cancers are urgently needed. Because many prostate cancers require the androgen dihydrotestosterone to proliferate, antiandrogens such as casodex (bicalutamide) are often the first line therapy for treatment of this disease. However, this drug and other clinically employed antiandrogens generally suffer from low affinity for the androgen receptor (AR), low selectivity across the nuclear hormone receptor superfamily, and do not achieve complete androgen blockade. As an alternative, mifepristone (RU486) is under investigation as a potential anticancer agent effective against prostate cancers. This drug is a highly potent antiprogestin (IC50 = 25 pM) but also exhibits potent antiglucocorticoid (IC50 = 2.2 nM) and antiandrogen (IC50 = 10 nM) activities. Although mifepristone is effective against prostate cancer cells in vivo, the use of this drug as a chronically administered anticancer agent is severely limited by its potent antiglucocorticoid activity. We investigated novel anticancer agents structurally related to mifepristone but that are designed to lack the antiglucocorticoid activity associated with this drug. Some compounds identified were more potent than casodex against LnCaP cells.