2. Academic Validation
  3. Synthesis of potent human DHRS11 inhibitors and their efficacy against androgen-dependent proliferation and sensitivity to AKT inhibitor Capivasertib of triple-negative breast cancer cells

Synthesis of potent human DHRS11 inhibitors and their efficacy against androgen-dependent proliferation and sensitivity to AKT inhibitor Capivasertib of triple-negative breast cancer cells

  • Eur J Med Chem. 2026 Apr 5:307:118649. doi: 10.1016/j.ejmech.2026.118649.
Yuri Miyamoto 1,  Wakana Hirai 2,  Tomofumi Saka 1,  Masatoshi Tanio 1,  Yudai Kudo 3,  Yuta Yoshino 1,  Yusuke Nakagawa 2,  Nao Kobayashi 2,  Sana Takada 4,  Takuya Okada 2,  Naoki Toyooka 2,  Mahmoud Kandeel 5,  Nobutada Tanaka 4,  Akira Ikari 1,  Satoshi Endo 6
Affiliations

Affiliations

  • 1 Laboratory of Biochemistry, Gifu Pharmaceutical University, Gifu, 501-1196, Japan.
  • 2 Graduate School of Pharma-Medical Sciences, University of Toyama, Toyama, 930-8555, Japan.
  • 3 United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, Gifu, 501-1194, Japan.
  • 4 School of Pharmacy, Kitasato University, Minato-ku, Tokyo, 108-8641, Japan.
  • 5 Department of Biomedical Sciences, College of Veterinary Medicine, King Faisal University, Al-Ahsa, 31982, Saudi Arabia.
  • 6 United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, Gifu, 501-1194, Japan; Center for One Medicine Innovative Translational Research (COMIT), Gifu University, Gifu, 501-1193, Japan; Preemptive Food Research Center, Gifu University, Gifu, 501-1193, Japan. Electronic address: endou.satoshi.n1@f.gifu-u.ac.jp.
PMID: 41679198 DOI: 10.1016/j.ejmech.2026.118649
Abstract

Triple-negative breast Cancer (TNBC) is a highly aggressive subtype of breast Cancer lacking Estrogen receptor (ER), Progesterone Receptor (PR), and HER2 expression. Among its heterogeneous subtypes, luminal androgen receptor-positive (LAR) TNBC is driven by androgen signaling and presents limited treatment options. We previously identified dehydrogenase/reductase SDR family member 11 (DHRS11) as a novel enzyme involved in androgen biosynthesis, and demonstrated that Kobochromone A (KC-A), a polyphenol isolated from Carex kobomugi, inhibited androgen-driven proliferation in LAR TNBC cells via DHRS11 inhibition and AR downregulation. In this study, we synthesized 23 structural derivatives of KC-A and identified WH23 as the most potent DHRS11 inhibitor (IC50 = 37 nM). Molecular docking and MM-PBSA analysis revealed that the 2'-hydroxy group of WH23 forms a hydrogen bond with His210 of DHRS11, which was validated by site-directed mutagenesis. WH23 suppressed AR mRNA and protein expression, reduced 11-ketodihydrotestosterone (11KDHT)-induced c-Myc expression, and inhibited proliferation of MDA-MB-453 cells. Additionally, WH23 inhibited PI3K/Akt signaling, reducing phosphorylation of PDK1, Akt, mTOR, and ERK. Capivasertib (Cap), a clinically approved pan-AKT inhibitor, induced DHRS11 expression in MDA-MB-453 cells. Although Cap and WH23 did not show synergistic cytotoxicity in parental cells, Cap-resistant (Cap-R) cells, which exhibited elevated DHRS11 and c-Myc expression, showed significant sensitivity to the combination. In Cap-R cells, the combination of Cap and WH23 significantly induced Apoptosis, demonstrating a synergistic Anticancer effect. These findings establish WH23 as a dual-acting compound targeting both androgen biosynthesis and AR signaling, with potential to overcome Akt Inhibitor resistance in LAR TNBC.

Keywords

Androgen signaling; Capivasertib; DHRS11; Kobochromone A; Triple-negative breast cancer.

Figures
Products
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