7C7H

Crystal structures of AKR1C3 ternary complex with NADP+ and the chromene derivative 2l

Summary for 7C7H

• Entry DOI: 10.2210/pdb7c7h/pdb
• Descriptor: Aldo-keto reductase family 1 member C3, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, 2-azanylidene-N-(3-ethylphenyl)-8-oxidanyl-chromene-3-carboxamide, ... (4 entities in total)
• Functional Keywords: cancer, oxidoreductase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 76204.19

Authors

Irie, K.,Toyooka, N.,Endo, S. (deposition date: 2020-05-25, release date: 2020-09-23, Last modification date: 2023-11-29)

Primary citation

Endo, S.,Oguri, H.,Segawa, J.,Kawai, M.,Hu, D.,Xia, S.,Okada, T.,Irie, K.,Fujii, S.,Gouda, H.,Iguchi, K.,Matsukawa, T.,Fujimoto, N.,Nakayama, T.,Toyooka, N.,Matsunaga, T.,Ikari, A.
Development of Novel AKR1C3 Inhibitors as New Potential Treatment for Castration-Resistant Prostate Cancer.
J.Med.Chem., 63:10396-10411, 2020

PubMed 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. 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, -(4-fluorophenyl)-8-hydroxy-2-imino-2-chromene-3-carboxamide (), and synthesized its derivatives with IC 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 and . The inhibitors suppressed proliferation of prostate cancer 22Rv1 and PC3 cells through both androgen-dependent and androgen-independent mechanisms. Additionally, and 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).

PubMed: 32847363
DOI: 10.1021/acs.jmedchem.0c00939

Experimental method

X-RAY DIFFRACTION (1.86 Å)