Anticancer Inhibitors of AR-Mediated Gene Expression
Final rept. 1 Nov 2004-31 Oct 2006
PENNSYLVANIA STATE UNIV UNIVERSITY PARK
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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.
- Medicine and Medical Research