Lethal activity of BRD4 PROTAC degrader QCA570 against bladder cancer cells

Qiang Wang; Baohu Li; Wenkai Zhang; Zhuoyue Li; Bo Jiang; Sichuan Hou; Shumin Ma; Chong Qin

doi:10.3389/fchem.2023.1121724

Lethal activity of BRD4 PROTAC degrader QCA570 against bladder cancer cells

Front Chem. 2023 Jan 17:11:1121724. doi: 10.3389/fchem.2023.1121724. eCollection 2023.

Authors

Qiang Wang^{1

2}, Baohu Li², Wenkai Zhang², Zhuoyue Li², Bo Jiang¹, Sichuan Hou¹, Shumin Ma², Chong Qin^{2

3}

Affiliations

¹ Department of Urology, Qingdao Municipal Hospital, Qingdao University, Qingdao, China.
² Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, China.
³ Laboratory for Marine Drugs and Bioproducts, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China.

Abstract

Bladder cancer is the most common malignancy of the urinary system. Efforts to identify innovative and effective therapies for bladder cancer are urgently needed. Recent studies have identified the BRD4 protein as the critical factor in regulation of cell proliferation and apoptosis in bladder cancer, and it shows promising potential for pharmacologic treatment against bladder cancer. In this study, we have evaluated the biological function of QCA570, a novel BET degrader, on multiple bladder cancer cells and explore its underlying mechanisms. QCA570 potently induces degradation of BRD4 protein at nanomolar concentrations, with a DC₅₀ of ∼ 1 nM. It decreases EZH2 and c-MYC levels by transcriptional suppression and protein degradation. Moreover, the degrader significantly induces cell apoptosis and cycle arrest and shows antiproliferation activity against bladder cancer cells. These findings support the potential efficacy of QCA570 on bladder cancer.

Keywords: BRD4; PROTAC; QCA570; bladder cancer; targeted therapy.

Grants and funding

This work was supported by the grants from National Natural Science Foundation of China (22107095), Natural Science Foundation of Shandong Province, China (ZR2021YQ53).