Discovery of novel flavonoid-based CDK9 degraders for prostate cancer treatment via a PROTAC strategy
Tizhi Wu1, Zhiming Zhang1, Guangyue Gong1
1Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, PR China.
Abstract:
CDK9 plays a vital role in regulating RNA transcription and significantly impacts the expression of short-lived proteins such as Mcl-1 and c-Myc. Thus, targeting CDK9 holds great promise for the development of antitumor drugs. Natural flavonoid derivatives have recently gained considerable attention in the field of antitumor drug research due to their broad bioactivity and low toxicity. In this study, the PROTAC strategy was used to perform structural modifications of the flavonoid derivative LWT-111 to design a series of flavonoid-based CDK9 degraders. Notably, compound CP-07 emerged as a potent CDK9 degrader, effectively suppressing the proliferation and colony formation of 22RV1 cells by downregulating Mcl-1 and c-Myc. Moreover, CP-07 exhibited significant tumor growth inhibition with a TGI of 75.1% when administered at a dose of 20 mg/kg in the 22RV1 xenograft tumor model. These findings demonstrated the potential of CP-07 as a powerful flavonoid-based CDK9 degrader for prostate cancer therapy.
Insights
Researchers developed a novel flavonoid-based compound, CP-07, that effectively targets CDK9 (Cyclin-Dependent Kinase 9) to inhibit prostate cancer cell growth. This new drug candidate shows significant potential for cancer therapy by downregulating key proteins.
Area of Science:
- Molecular Biology
- Medicinal Chemistry
- Oncology
Background:
- Cyclin-Dependent Kinase 9 (CDK9) is crucial for RNA transcription and regulates short-lived proteins like Mcl-1 and c-Myc.
- Targeting CDK9 is a promising strategy for developing novel antitumor drugs.
- Natural flavonoid derivatives offer potential in cancer research due to their bioactivity and low toxicity.
Purpose of the Study:
- To design and synthesize novel flavonoid-based CDK9 degraders using the PROTAC strategy.
- To evaluate the efficacy of these compounds, particularly CP-07, in inhibiting prostate cancer cell proliferation and tumor growth.
Main Methods:
- Structural modification of the flavonoid derivative LWT-111 via PROTAC strategy.
- Assessment of CDK9 degradation and its effect on Mcl-1 and c-Myc expression in 22RV1 cells.
- In vivo evaluation of compound CP-07 in a 22RV1 xenograft tumor model.
Main Results:
- Compound CP-07 demonstrated potent CDK9 degradation activity.
- CP-07 effectively suppressed 22RV1 cell proliferation and colony formation by downregulating Mcl-1 and c-Myc.
- Significant tumor growth inhibition (75.1% TGI) was observed in the 22RV1 xenograft model at 20 mg/kg.
Conclusions:
- CP-07 is a potent flavonoid-based CDK9 degrader with significant antitumor activity.
- CP-07 shows promise as a therapeutic agent for prostate cancer treatment.
- The PROTAC strategy is effective in developing novel flavonoid-based targeted cancer therapies.
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