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

被引：11

作者：

He, Siyu ^{[1
,2
]}

Chu, Xianglin ^{[1
]}

Wu, Yujia ^{[3
]}

Jiang, Jiheng ^{[4
,5
]}

Fang, Pengfei ^{[4
,5
]}

Chen, Yuting ^{[1
]}

Liu, Yang ^{[1
]}

Qiu, Zhixia ^{[6
]}

Xiao, Yibei ^{[6
,7
,8
]}

Li, Zhiyu ^{[1
,6
]}

Pan, Di ^{[9
]}

Zhang, Qian ^{[6
,7
,8
]}

Xie, Huanfang ^{[1
]}

Xing, Shuaishuai ^{[1
]}

Feng, Feng ^{[10
]}

Liu, Wenyuan ^{[1
]}

Guo, Qinglong ^{[3
]}

Zhao, Li ^{[3
]}

Yang, Peng ^{[1
,6
]}

Sun, Haopeng ^{[1
]}

机构：

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

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

[3] China Pharmaceut Univ, Sch Basic Med & Clin Pharm, Jiangsu Key Lab Carcinogenesis & Intervent, State Key Lab Nat Med, Nanjing 210009, Peoples R China

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

[5] Chinese Acad Sci, Shanghai Inst Organ Chem, Ctr Excellence Mol Synth, State Key Lab Bioorgan & Nat Prod Chem, 345 Lingling Rd, Shanghai 200032, Peoples R China

[6] China Pharmaceut Univ, State Key Lab Nat Med, Jiangsu Key Lab Drug Design & Optimizat, Nanjing 210009, Peoples R China

[7] China Pharmaceut Univ, Sch Pharm, Dept Pharmacol, Nanjing 211198, Peoples R China

[8] China Pharmaceut Univ, Chongqing Innovat Inst, Chongqing, Peoples R China

[9] Guizhou Med Univ, Sch Pharmaceut Sci, Key Lab Optimal Utilizat Nat Med Resources, Guiyang 550025, Guizhou, Peoples R China

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

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2023年 / 66卷 / 14期

基金：

中国国家自然科学基金;

关键词：

NONSTEROIDAL ANTIINFLAMMATORY DRUGS; SELECTIVE INHIBITORS; DEHYDROGENASE ISOFORMS; REVEALS ROLES; POTENT; EXPRESSION; ANALOGS; CELLS; METABOLISM; ASP9521;

D O I：

10.1021/acs.jmedchem.3c00213

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Aldo-keto reductase 1C3 (AKR1C3) is correlated with tumordevelopmentand chemotherapy resistance. The catalytic activity of the enzymehas been recognized as one of the important factors in inducing anthracycline(ANT) resistance in cancer cells. Inhibition of AKR1C3 activity mayprovide a promising approach to restore the chemosensitivity of ANT-resistantcancers. Herein, a series of biaryl-containing AKR1C3 inhibitors hasbeen developed. The best analogue S07-1066 selectivelyblocked AKR1C3-mediated reduction of doxorubicin (DOX) in MCF-7 transfectedcell models. Furthermore, co-treatment of S07-1066 significantlysynergized DOX cytotoxicity and reversed the DOX resistance in MCF-7cells overexpressing AKR1C3. The potential synergism of S07-1066 over DOX cytotoxicity was demonstrated in vitro and in vivo. Our findings indicate that inhibitionof AKR1C3 potentially enhances the therapeutic efficacy of ANTs andeven suggests that AKR1C3 inhibitors may serve as effective adjuvantsto overcome AKR1C3-mediated chemotherapy resistance in cancer treatment.

引用

页码：9537 / 9560

页数：24

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