Discovery of Highly Potent AKR1C3 Inhibitors Treating Sorafenib-Resistant Hepatocellular Carcinoma

被引：0

作者：

Xing, Shuaishuai ^{[1
]}

Jiang, Jiheng ^{[6
]}

Chu, Xianglin ^{[1
]}

Wang, Xiaolong ^{[1
]}

Wang, Zhiqiang ^{[2
]}

Li, Xinyu ^{[1
]}

Lv, Bingbing ^{[2
]}

Guo, Can ^{[1
]}

He, Siyu ^{[3
]}

Wang, Leyan ^{[1
]}

Zhang, Chenyu ^{[1
]}

Guo, Qinglong ^{[4
,5
]}

Zhao, Li ^{[4
]}

Fang, Pengfei ^{[6
,7
]}

Feng, Feng ^{[8
]}

Sun, Haopeng ^{[1
]}

机构：

[1] China Pharmaceut Univ, Sch Pharm, Nanjing 211198, Peoples R China

[2] Nanjing Univ Chinese Med, Sch Pharm, Nanjing 210023, Peoples R China

[3] Guizhou Med Univ, Guizhou Prov Engn Technol Res Ctr Chem Drug R&D, Guiyang 550004, Peoples R China

[4] China Pharmaceut Univ, Sch Basic Med & Clin Pharm, Nanjing 211198, Jiangsu, Peoples R China

[5] China Pharmaceut Univ, Jiangsu Key Lab Carcinogenesis & Intervent, Nanjing 210009, Jiangsu, Peoples R China

[6] Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Chem & Mat Sci, Hangzhou 310024, Peoples R China

[7] Chinese Acad Sci, Univ Chinese Acad Sci, Shanghai Inst Organ Chem, State Key Lab Chem Biol, 345 Lingling Rd, Shanghai 200032, Peoples R China

[8] Nanjing Med Univ, Sch Pharm, Nanjing 211166, Peoples R China

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2025年 / 68卷 / 07期

基金：

中国国家自然科学基金;

关键词：

ALDO-KETO REDUCTASE; EXPRESSION; CANCER; CELLS;

D O I：

10.1021/acs.jmedchem.4c03035

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Aldo-keto reductase 1C3 (AKR1C3) plays a key role in tumor progression and chemotherapy resistance, particularly in sorafenib-resistant hepatocellular carcinoma (HCC). Targeting AKR1C3 represents a promising strategy to restore chemosensitivity in resistant HCC. Previous research identified the lead compound S07-2005 through a cascade virtual screening approach (AKR1C3 IC50 = 130 +/- 30 nM, SI (selective index) > 77). Using cocrystal-guided drug design, 30 was optimized to adopt an "L"-shaped conformation targeting AKR1C3 ' s subpocket 1 (SP1) and oxyanion site (OS), enhancing inhibitory potency and selectivity (AKR1C3 IC50 = 5 +/- 1 nM, SI > 2000). It enhanced sorafenib-induced ROS generation, promoted apoptosis, and restored sorafenib sensitivity in HCC models. In combination with sorafenib, compound 30 restored sorafenib sensitivity in HCC both in vitro and in vivo. Additionally, compound 30 demonstrated a favorable safety profile and pharmacokinetic properties, suggesting its potential as an adjunct to overcome AKR1C3-mediated chemotherapy resistance in cancer treatment

引用

页码：7367 / 7389

页数：23

共 28 条

[1] Inhibitors of type 5 17β-hydroxysteroid dehydrogenase (AKR1C3): Overview and structural insights [J].

Byrns, Michael C. ;

Jin, Yi ;

Penning, Trevor M. .

JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY, 2011, 125 (1-2) :95-104

[2] Aldo-keto reductase 1C3 expression in MCF-7 cells reveals roles in steroid hormone and prostaglandin metabolism that may explain its over-expression in breast cancer [J].

Byrns, Michael C. ;

Duan, Ling ;

Lee, Seon Hwa ;

Blair, Ian A. ;

Penning, Trevor M. .

JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY, 2010, 118 (03) :177-187

[3] Discovery of an Aldo-Keto reductase 1C3 (AKR1C3) degrader [J].

Carmona, Angelica V. ;

Jonnalagadda, Shirisha ;

Case, Alfie M. ;

Maddeboina, Krishnaiah ;

Jonnalagadda, Sravan K. ;

Dow, Louise F. ;

Duan, Ling ;

Penning, Trevor M. ;

Trippier, Paul C. .

COMMUNICATIONS CHEMISTRY, 2024, 7 (01)

[4] AKR1C3 silencing inhibits autophagy-dependent glycolysis in thyroid cancer cells by inactivating ERK signaling [J].

Gao, Ying ;

Tao, Weijie ;

Wang, Shoujun ;

Duan, Ran ;

Zhang, Zhendong .

DRUG DEVELOPMENT RESEARCH, 2024, 85 (01)

[5] DAB2IP regulates intratumoral testosterone synthesis and CRPC tumor growth by ETS1/AKR1C3 signaling [J].

Gu, Yanan ;

Wu, Shiqi ;

Chong, Yue ;

Guan, Bing ;

Li, Lei ;

He, Dalin ;

Wang, Xinyang ;

Wang, Bin ;

Wu, Kaijie .

CELLULAR SIGNALLING, 2022, 95

[6] Development of Biaryl-Containing Aldo-Keto Reductase 1C3 (AKR1C3) Inhibitors for Reversing AKR1C3-Mediated Drug Resistance in Cancer Treatment [J].

He, Siyu ;

Chu, Xianglin ;

Wu, Yujia ;

Jiang, Jiheng ;

Fang, Pengfei ;

Chen, Yuting ;

Liu, Yang ;

Qiu, Zhixia ;

Xiao, Yibei ;

Li, Zhiyu ;

Pan, Di ;

Zhang, Qian ;

Xie, Huanfang ;

Xing, Shuaishuai ;

Feng, Feng ;

Liu, Wenyuan ;

Guo, Qinglong ;

Zhao, Li ;

Yang, Peng ;

Sun, Haopeng .

JOURNAL OF MEDICINAL CHEMISTRY, 2023, 66 (14) :9537-9560

[7] Discovery of Novel Aldo-Keto Reductase 1C3 Inhibitors as Chemotherapeutic Potentiators for Cancer Drug Resistance [J].

He, Siyu ;

Liu, Yang ;

Chu, Xianglin ;

Li, Qi ;

Lyu, Weiping ;

Liu, Yijun ;

Xing, Shuaishuai ;

Feng, Feng ;

Liu, Wenyuan ;

Guo, Qinglong ;

Zhao, Li ;

Sun, Haopeng .

ACS MEDICINAL CHEMISTRY LETTERS, 2022, 13 (08) :1286-1294

[8] Hepatotoxicity of AKR1C3 Inhibitor BAY1128688: Findings from an Early Terminated Phase IIa Trial for the Treatment of Endometriosis [J].

Hilpert, Jan ;

Groettrup-Wolfers, Esther ;

Kosturski, Hristiyan ;

Bennett, Laura ;

Barnes, Catriona L. K. ;

Gude, Kerstin ;

Gashaw, Isabella ;

Reif, Stefanie ;

Steger-Hartmann, Thomas ;

Scheerans, Christian ;

Solms, Alexander ;

Rottmann, Antje ;

Mao, Guangping ;

Chapron, Charles .

DRUGS IN R&D, 2023, 23 (03) :221-237

[9] Quantitative Evaluation of the Contribution of Each Aldo-Keto Reductase and Short-Chain Dehydrogenase/Reductase Isoform to Reduction Reactions of Compounds Containing a Ketone Group in the Human Liver [J].

Ichida, Hiroyuki ;

Fukami, Tatsuki ;

Amai, Keito ;

Suzuki, Kohei ;

Mishiro, Kenji ;

Takano, Shiori ;

Obuchi, Wataru ;

Zhang, Zhengyu ;

Watanabe, Akiko ;

Nakano, Masataka ;

Watanabe, Kengo ;

Nakajima, Miki .

DRUG METABOLISM AND DISPOSITION, 2023, 51 (01) :17-28

[10] 17β-hydroxysteroid dehydrogenase 14 affects estradiol levels in breast cancer cells and is a prognostic marker in estrogen receptor-positive breast cancer [J].

Jansson, Agneta K. ;

Gunnarsson, Cecilia ;

Cohen, Maja ;

Sivik, Tove ;

Stal, Olle .

CANCER RESEARCH, 2006, 66 (23) :11471-11477

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