Regression of Castration-Resistant Prostate Cancer by a Novel Compound HG122.

Xiaonan Cong,Yundong He,Tao Ding,Zhengfang Yi,Dingxiang Wang,Haigang Wu,Ting Shao,Yongrui Liu,Shihong Peng,Jianghua Zheng,Mingyao Liu

doi:10.3389/fonc.2021.650919

Abstract

Prostate cancer (PCa) is a common aggressive disease worldwide which usually progresses into incurable castration-resistant prostate cancer (CRPC) in most cases after 18–24 months treatment. Androgen receptor (AR) has been considered as a crucial factor involved in CRPC and the study of AR as a potential therapeutic target in CRPC may be helpful in disease control and life-cycle management. In this study, we identified a potent small molecule compound, HG122, that suppressed CRPC cells proliferation and metastasis, and inhibited tumor growth both in subcutaneous and orthotopic tumor model. In addition, HG122 reduced the mRNA expression of PSA and TMPRSS2 which are target genes of AR, resulting in cell growth inhibition and metastasis suppression of CRPC, without affecting the expression of AR mRNA level. Mechanically, HG122 promoted AR protein degradation through the proteasome pathway impairing the AR signaling pathway. In conclusion, HG122 overcomes enzalutamide (ENZ) resistance in CRPC both in vitro and in vivo, thus suggesting HG122 is a potential candidate for the clinical prevention and treatment of CRPC.

Highlights

Androgen receptor (AR), a member of the nuclear hormone receptor superfamily [19,20,21], is either activated by binding of dihydrotestosterone (DHT) [22, 23] or constitutively activated
These findings have led to clinical development and adoption of new therapeutic methods targeting AR signaling pathways for Prostate cancer (PCa) but for castration-resistant prostate cancer (CRPC)
To identify compounds that block the transcriptional activities of AR, we used the MMTV-luciferase reporter system containing AR-binding elements [30] to screen a library of synthesized compounds available in our laboratory and identified a smallmolecule compound termed HG122 (Structure in Figure 1A), that potently reduced the transcriptional activities of AR

Summary

Introduction

AR, a member of the nuclear hormone receptor superfamily [19,20,21], is either activated by binding of dihydrotestosterone (DHT) [22, 23] or constitutively activated. While recent evidences show that in CRPC, the AR signaling pathway is still active even when serum androgen is at castrated levels. AR can be activated through a variety of mechanisms, including: primary androgen synthesis [26], AR caused by AR overexpression, mutation or splicing [27], interaction of co-acting factors, and post-translational modification [28]. These findings have led to clinical development and adoption of new therapeutic methods targeting AR signaling pathways for PCa but for CRPC. Agents that inhibit AR signaling might be extremely useful for treating CRPC

Methods

Results

Conclusion