The hypothesis of this proposal is that blocking the effect of androgens with inhibitors that act through multiple mechanisms will result in more effective treatment for prostate cancer. The long term goal is to identify and characterize compounds with strong inhibition of androgen biosynthesis, and receptor mediated transcription that are likely to provide superior anti-tumor activity in androgen-sensitive prostate cancer. New compounds will be identified through pharmacophore-based molecular modeling techniques, and along with novel compounds previously synthesized in our lab, assayed for: inhibition of 17a-hydroxylyase/C17,20- lyase, a key enzyme in androgen biosynthesis, inhibition of prostate cancer cell proliferation, and competitive inhibition of androgen receptor binding / transcriptional activation. To further elucidate the mechanisms of action of androgen synthesis inhibitors, apoptotic and protein expression profiles will be examined. By examining apoptotic signaling pathways activated by lyase inhibitors, new targets for drug therapy may be revealed.
