Aldo–keto
reductase (AKR) 1C3 catalyzes the synthesis of
active androgens that promote the progression of prostate cancer.
AKR1C3 also contributes to androgen-independent cell proliferation
and survival through the metabolism of prostaglandins and reactive
aldehydes. Because of its elevation in castration-resistant prostate
cancer (CRPC) tissues, AKR1C3 is a promising therapeutic target for
CRPC. In this study, we found a novel potent AKR1C3 inhibitor, N-(4-fluorophenyl)-8-hydroxy-2-imino-2H-chromene-3-carboxamide (2d), and synthesized its derivatives
with IC50 values of 25–56 nM and >220-fold selectivity
over other AKRs (1C1, 1C2, and 1C4). The structural factors for the
inhibitory potency were elucidated by crystallographic study of AKR1C3
complexes with 2j and 2l. The inhibitors
suppressed proliferation of prostate cancer 22Rv1 and PC3 cells through
both androgen-dependent and androgen-independent mechanisms. Additionally, 2j and 2l prevented prostate tumor growth in
a xenograft mouse model. Furthermore, the inhibitors significantly
augmented apoptotic cell death induced by anti-CRPC drugs (abiraterone
or enzalutamide).