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

• Published in: Acta pharmacologica Sinica Vol. 43; no. 4; pp. 1024 - 1032
• Main Authors: Wang, Hong, Chang, Zhe, Cai, Guo-di, Yang, Ping, Chen, Jiang-he, Yang, Shan-shu, Guo, Yin-feng, Wang, Ming-yu, Zheng, Xue-hua, Lei, Jin-ping, Liu, Pei-qing, Zhao, De-peng, Wang, Jun-jian
• Format: Journal Article
• Language: English
• Published: Singapore Springer Singapore 01.04.2022; Nature Publishing Group
• Subjects: Androgen receptors; Androgens; Anti-inflammatory agents; Antitumor activity; Apoptosis; Biomedical and Life Sciences; Biomedicine; Castration; Cell Line, Tumor; Cell Proliferation; Cell survival; Cell viability; Cholecystokinin; Heterografts; Humans; Immunology; Indomethacin; Indomethacin - pharmacology; Indomethacin - therapeutic use; Inflammation; Internal Medicine; Male; Medical Microbiology; Pharmacology/Toxicology; Prostate cancer; Prostatic Neoplasms, Castration-Resistant - drug therapy; Prostatic Neoplasms, Castration-Resistant - metabolism; Prostatic Neoplasms, Castration-Resistant - pathology; Receptors, Androgen - metabolism; Therapeutic targets; Tumors; Vaccine; Xenograft Model Antitumor Assays; Xenografts; androgen receptor (AR); indomethacin derivatives; CZ-212-3; patient-derived xenograft model (PDX); castration-resistant prostate cancer (CRPC)
• ISSN: 1671-4083; 1745-7254
• DOI: 10.1038/s41401-021-00738-w

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.