2. Academic Validation
  3. Development of Novel AKR1C3 Inhibitors as New Potential Treatment for Castration-Resistant Prostate Cancer

Development of Novel AKR1C3 Inhibitors as New Potential Treatment for Castration-Resistant Prostate Cancer

  • J Med Chem. 2020 Sep 24;63(18):10396-10411. doi: 10.1021/acs.jmedchem.0c00939.
Satoshi Endo 1,  Hiroaki Oguri 1,  Jin Segawa 1,  Mina Kawai 1,  Dawei Hu 2,  Shuang Xia 2,  Takuya Okada 2,  Katsumasa Irie 3 4,  Shinya Fujii 5,  Hiroaki Gouda 6,  Kazuhiro Iguchi 7,  Takuo Matsukawa 8,  Naohiro Fujimoto 8,  Toshiyuki Nakayama 9,  Naoki Toyooka 2,  Toshiyuki Matsunaga 10,  Akira Ikari 1
Affiliations

Affiliations

  • 1 Laboratory of Biochemistry, Gifu Pharmaceutical University, Gifu 501-1196, Japan.
  • 2 Graduate School of Innovative Life Science, University of Toyama, Toyama 930-8555, Japan.
  • 3 Cellular and Structural Physiology Institute, Nagoya University, Furo-cho, Chikusa, Nagoya 464-8601, Japan.
  • 4 Graduate School of Pharmaceutical Sciences, Nagoya University, Furo-cho, Chikusa, Nagoya 464-8601, Japan.
  • 5 Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Tokyo 101-0062, Japan.
  • 6 School of Pharmacy, Showa University, Tokyo 142-8555, Japan.
  • 7 Laboratory of Community Pharmacy, Department of Pharmacy, Gifu Pharmaceutical University, Gifu 501-1196, Japan.
  • 8 Department of Urology, University of Occupational and Environmental Health, Kitakyushu 807-8555, Japan.
  • 9 Department of Pathology, University of Occupational and Environmental Health, Kitakyushu 807-8555, Japan.
  • 10 Education Center of Green Pharmaceutical Sciences, Gifu Pharmaceutical University, Gifu 502-8585, Japan.
PMID: 32847363 DOI: 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. 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).

Figures
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z