Development of Novel AKR1C3 Inhibitors as New Potential Treatment for Castration-Resistant Prostate Cancer
- 27 August 2020
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 63 (18), 10396-10411
- https://doi.org/10.1021/acs.jmedchem.0c00939
Abstract
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. Due to 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 -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).Funding Information
- Japan Agency for Medical Research and Development (JP17lm0203002)
- Japan Society for the Promotion of Science (17K11151, JP26460149)
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