94% of researchers rate our articles as excellent or good
Learn more about the work of our research integrity team to safeguard the quality of each article we publish.
Find out more
ORIGINAL RESEARCH article
Front. Pharmacol.
Sec. Experimental Pharmacology and Drug Discovery
Volume 16 - 2025 | doi: 10.3389/fphar.2025.1560559
A combinatorial screening protocol for identifying novel and highly potent dual-target inhibitor of BRD4 and STAT3 for kidney cancer therapy
Provisionally accepted- 1 Huai'an Cancer Hospital, Huai'an, China
- 2 China Pharmaceutical University, Nanjing, Jiangsu Province, China
- 3 The Affiliated Taizhou People’s Hospital of Nanjing Medical University, Taizhou, China
Concurrent inhibition of bromodomain-containing protein 4 (BRD4) and signal transductor and activator of transcription 3 (STAT3) could potentially be an effective strategy against renal cell carcinoma (RCC). Here, we successfully identified five dualtargeted BRD4/STAT3 inhibitors (BSTs 1-5) using a combinatorial screening protocol.Particularly, BST-4 was the most potent inhibitor simultaneously targeting BRD4 (IC50 = 2.45 ± 0.11 nM) and STAT3 (IC50 = 8.07 ± 0.51 nM). MD simulation indicated that BST-4 stably bound to the active sites of BRD4 and STAT3. The cytotoxicity assays exhibited that BST-4 had a significant antiproliferative activity against RCC cell lines, especially CAKI-2 cells (IC50 = 0.76 ± 0.05 μM). Moreover, in vivo experiments revealed that BST-4 more effectively inhibited the growth of xenograft tumors compared with positive controls RVX-208 and CJ-1383. Overall, these data indicated that BST-4 could be a promising candidate compound for RCC therapy.
Keywords: Renal cell carcinoma, Bromodomain-containing Protein 4 (BRD4), signal transductor and activator of transcription 3 (STAT3), Virtual Screening, Dual-targeted inhibitors
Received: 14 Jan 2025; Accepted: 10 Feb 2025.
Copyright: © 2025 Zhang, Wu, Geng, Guan, Niu, Li and Zhu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Lusha Zhu, The Affiliated Taizhou People’s Hospital of Nanjing Medical University, Taizhou, China
Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.