2. Academic Validation
  3. Discovery and biological evaluation of novel androgen receptor antagonist for castration-resistant prostate cancer

Discovery and biological evaluation of novel androgen receptor antagonist for castration-resistant prostate cancer

  • Eur J Med Chem. 2019 Jun 1;171:265-281. doi: 10.1016/j.ejmech.2019.03.041.
Jiang Yu 1,  Lanxi Zhang 1,  Guoyi Yan 2,  Peiting Zhou 1,  Chaoguo Cao 1,  Fei Zhou 1,  Xinghai Li 3,  Yuanwei Chen 4
Affiliations

Affiliations

  • 1 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, China.
  • 2 Department of Hepatobiliary Pancreatic Surgery, Henan Province People's Hospital, Zhengzhou, 450003, China.
  • 3 Hinova Pharmaceuticals Inc, 4th Floor, Building RongYao A, No. 5, Keyuan South Road, Chengdu, 610041, China.
  • 4 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, China; Hinova Pharmaceuticals Inc, 4th Floor, Building RongYao A, No. 5, Keyuan South Road, Chengdu, 610041, China. Electronic address: [email protected].
PMID: 30925341 DOI: 10.1016/j.ejmech.2019.03.041
Abstract

Prostate Cancer (PC) is the second most common malignancy in men worldwide. Among current therapies, two antiandrogens, Abiraterone Acetate and Enzalutamide (Enza) have become the standard of care for patients with metastatic castration-resistant prostate Cancer (mCRPC). Here, we designed and synthesized a new series of nonsteroidal compounds deriving from the hybridization of Abiraterone (Abi) and Enzalutamide, among which compound 4a featuring the diphenylamine scaffold was identified as a potent and cell selective Androgen Receptor (AR) antagonist. In cell proliferation assays, compound 4a exhibited better antiproliferative activities than Enzalutamide against AR-overexpressing VCaP cells and 22Rv1 cells bearing H874Y-mutated AR. In addition, 4a suppressed the activity of AR-F876L mutant that confers resistance to Enzalutamide and efficiently blocked R1881-induced PSA and FKBP5 gene expression. In competitive binding assay, compound 4a displayed higher binding affinity to AR than Enzalutamide. These results suggest compound 4a as a potential candidate to treat Enza-resistant CRPC.

Keywords

Androgen receptor antagonist; Castration-resistant prostate cancer; Enzalutamide resistance; F876L mutation.

Figures
Products