The novel indomethacin derivative CZ-212-3 exerts antitumor effects on castration-resistant prostate cancer by degrading androgen receptor and its variants

Hong Wang1, Zhe Chang1, Guo-di Cai1, Ping Yang2,3, Jiang-he Chen1, Shan-shu Yang4, Yin-feng Guo1, Ming-yu Wang1, Xue-hua Zheng4, Jin-ping Lei1, Pei-qing Liu1,5,6, De-peng Zhao1, Jun-jian Wang1,5,6
1 School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
2 State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
3 Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
4 Key Laboratory of Molecular Target and Clinical Pharmacology, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou 510006, China
5 Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
6 National-Local Joint Engineering Laboratory of Druggability and New Drugs Evaluation, Sun Yat-sen University, Guangzhou 510006, China
Correspondence to: De-peng Zhao:, Jun-jian Wang:,
DOI: 10.1038/s41401-021-00738-w
Received: 2 March 2021
Accepted: 29 June 2021
Advance online: 28 July 2021


Androgen receptor (AR) serves as a main therapeutic target for prostate cancer (PCa). However, resistance to anti-androgen therapy (SAT) inevitably occurs. Indomethacin is a nonsteroidal anti-inflammatory drug that exhibits activity against prostate cancer. Recently, we designed and synthesized a series of new indomethacin derivatives (CZ compounds) via Pd (II)-catalyzed synthesis of substituted N-benzoylindole. In this study, we evaluated the antitumor effect of these novel indomethacin derivatives in castration- resistant prostate cancer (CRPC). Upon employing CCK-8 cell viability assays and colony formation assays, we found that these derivatives had high efficacy against CRPC tumor growth in vitro. Among these derivatives, CZ-212-3 exhibited the most potent efficacy against CRPC cell survival and on apoptosis induction. Mechanistically, CZ-212-3 significantly suppressed the expression of AR target gene networks by degrading AR and its variants. Consistently, CZ-212-3 significantly inhibited tumor growth in CRPC cell line-based xenograft and PDX models in vivo. Taken together, the data show that the indomethacin derivative CZ-212-3 significantly inhibited CRPC tumor growth by degrading AR and its variants and could be a promising agent for CRPC therapy.
Keywords: castration-resistant prostate cancer (CRPC); indomethacin derivatives; CZ-212-3; androgen receptor (AR); patient-derived xenograft model (PDX)

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