Publication Details (including relevant citation information):
242nd ACS National Meeting held at Denver, Colorado, August 28 – September 1, 2011. PAPER ID: MEDI-35
The androgen receptor (AR) is a critical mediator of prostate cancer (PC) proliferation at virtually all stages of PC, including the dreaded castration-resistant stage. Selective AR down-regulators (SARDs) reduce AR protein levels as well as block AR activity and therefore are promising agents for the treatment of PC. Our clinical candidate novel VN/124-1 (TOK-001) is a potent CYP17 inhibitor/antiandrogen with modest AR down-regulating activity (EC50 ~ 10 µM). In the present study we used VN/124-1 to conduct lead optimization to develop a novel class of AR down-regulating agents. A series of new compounds were designed, synthesized and evaluated for their abilities to suppress AR expression in LNCaP cells and inhibition of LNCaP cell viability by Western blot analysis and MTT assay, respectively. Our design strategy involved systematic modification of rings A, B or D; and modifications at C-3, C-16 and C-17 of our lead VN/124-1, resulted in novel potent anti-PC agents.