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.

CDK9 在调节 RNA 转录中发挥着至关重要的作用，并显着影响 Mcl-1 和c - Myc 等短寿命蛋白的表达。因此，靶向CDK9对于抗肿瘤药物的开发具有广阔的前景。天然黄酮类衍生物因其广泛的生物活性和低毒性而近年来在抗肿瘤药物研究领域受到广泛关注。本研究采用PROTAC策略对类黄酮衍生物LWT-111进行结构修饰，设计出一系列基于类黄酮的CDK9降解剂。值得注意的是，化合物CP-07作为一种有效的 CDK9 降解剂，通过下调 Mcl-1 和c -Myc 有效抑制 22RV1 细胞的增殖和集落形成。此外，在 22RV1 异种移植肿瘤模型中，当以 20 mg/kg 剂量给药时，CP-07表现出显着的肿瘤生长抑制作用，TGI 为 75.1%。这些发现证明了CP-07作为一种强大的基于类黄酮的 CDK9 降解剂用于前列腺癌治疗的潜力。