The novel CDK9 inhibitor, XPW1, alone and in combination with BRD4 inhibitor JQ1, for the treatment of clear cell renal cell carcinoma
- Br J Cancer. 2023 Oct 26. doi: 10.1038/s41416-023-02464-y.
- 1. Fujian Provincial Key Laboratory of Innovative Drug Target Research and State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, 361102, Xiamen, China.
- 2. College of Arts, Sichuan University, 610207, Chengdu, China.
- 3. School of Medicine, Xiamen University, 361102, Xiamen, China.
- 4. Jiangxi Cancer Hospital (The Second Affiliated Hospital of Nanchang Medical Colloge), 519 East Beijing Rd, 330029, Nanchang, Jiangxi, China.
- 5. Fujian Provincial Key Laboratory of Innovative Drug Target Research and State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, 361102, Xiamen, China. [email protected].
- 6. Fujian Provincial Key Laboratory of Innovative Drug Target Research and State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, 361102, Xiamen, China. [email protected].
- 7. Fujian Provincial Key Laboratory of Innovative Drug Target Research and State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, 361102, Xiamen, China. [email protected].
- # Contributed equally.
Background: Clear cell renal cell carcinoma (ccRCC) is a highly lethal malignancy with few therapeutic options. Cyclin‑dependent kinase 9 (CDK9), a potential therapeutic target of many cancers, has been recently observed to be upregulated in ccRCC patients. Therefore, we aimed to investigate the therapeutic potential of CDK9 in ccRCC and develop a novel CDK9 Inhibitor with low toxicity for ccRCC treatment.
Methods: The expression of CDK9 in ccRCC was checked using the online database and tissue microarray analysis. shRNA-mediated CDK9 knockdown and CDK Inhibitor were applied to evaluate the effect of CDK9 on ccRCC. Medicinal chemistry methods were used to develop a new CDK9 Inhibitor with drugability. RNA-seq and ChIP-seq experiments were conducted to explore the mechanism of action. MTS, western blotting, and colony formation assays were performed to evaluate the anti-ccRCC effects of CDK9 knockdown and inhibition in vitro. The in vivo anti-tumour efficacy was evaluated in a xenograft model.
Results: CDK9 is overexpressed and associated with poor survival in ccRCC. Knockdown or inhibition of CDK9 significantly suppressed ccRCC cells. XPW1 was identified as a new potent and selective CDK9 Inhibitor with excellent anti-ccRCC activity and low toxicity. In mechanism, XPW1 transcriptionally inhibited DNA repair programmes in ccRCC cells, resulting in an excellent anti-tumour effect. CDK9 and BRD4 were two highly correlated transcriptional regulators in ccRCC patients, and the BRD4 Inhibitor JQ1 enhanced XPW1's anti-ccRCC effects in vitro and in vivo.
Conclusions: This work provides valuable insights into the therapeutic potential of CDK9 in ccRCC. The CDK9 Inhibitor XPW1 would be a novel therapeutic agent for targeting ccRCC, alone or in rational combinations.