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4 Birds 1 Stone to Inhibit 5androstane-3alpha,17beta-diol Conversion to DHT
Technical Report,15 Aug 2015,14 Aug 2016
Health Research, Inc. Buffalo United States
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Prostate cancer growth and survival relies on the interaction between androgen receptor and the testicular androgens, testosterone or dihydrotestosterone DHT. Men diagnosed with advanced prostate cancer or failure potentially curative therapy are treated with androgen deprivation therapy ADT. ADT is palliative and CaP recurs. One mechanism that contributes to CaP recurrence is androgen metabolism and our laboratory is studies the primary backdoor androgen metabolism pathway. The terminal step of the primary backdoor androgen metabolism pathway involves the conversion of androstanediol to DHT. There are no inhibitors that inhibit the enzymes, HSD17B6, RDH16, DHRS9 or RDH5, that metabolize androstanediol to DHT. All 4 enzymes have a common conserved catalytic site. The goal of these studies is to identify an inhibitor that impairs all 4 enzymes. During this award period, we have identified the residues responsible for enzyme activity and developed a 3 step inhibitor screen to identify inhibitors against the 4 enzymes.
APPROVED FOR PUBLIC RELEASE