The goal of this project is to develop compounds with characteristics that are likely to provide effective antitumor activity against androgen dependent prostatic cancer. Our strategy is to identify compounds, which achieve total androgen blockade. We have discovered a number of potent inhibitors of 17alpha-hydroxylase/C17,20-lyase (CYP17). Several of these were found to have multiple activities. Some inhibit 5a- reductase and/or are antiandrogens. VN/85-1, VN/87-1, and L-39 are the three most potent and best characterized compounds to date. The compounds have significant antitumor activity in androgen dependent tumors in mouse xenograft models and cause marked reduction in androgen levels. The following specific aims are proposed in order to develop the most active inhibitors and complete preclinical studies of the lead compounds L-39, VN/85-1, and VN/87-1 and prepare them for Phase I trials.
The Specific Aims of the project are: 1. Metabolic studies of lead compounds: a. Predictive models of metabolism, b. Synthesis of radiolabeled inhibitors, and c. Metabolic studies; 2. To design and synthesize: a. Analogs of current inhibitors to improve metabolic stability and increase efficacy and b. Non-steroidal inhibitors based on a molecular modeling approach; 3. To evaluate analogs and new compounds for inhibition of 17alpha-hydroxylase/ C17,20-lyase and all potent inhibitors for 5alpha -reductase Type I and Type II inhibition; 4. To determine the effects of the CYP17 inhibitors on androgen dependent growth in prostate cancer cells; 5. To determine whether the CYP17 inhibitors are agonists or antagonists of mutant or wild type androgen receptors using binding and transcriptional activation assays; and 6. To optimize the antitumor efficacy of the most potent inhibitors in mouse xenograft models with human prostate cancers (LAPC-4 and LNCaP androgen dependent tumors): a. Determine effective doses, scheduling, and route of administration and b. Compare the effect of lead inhibitors and castration on apoptosis to identify the best compound.
