Abstract：
Degradation of target proteins has been considered to be a promising therapeutic approach, but the rational design of compounds for degradation remains a challenge. In this study, we reasonably designed and synthesized only 10 compounds to discover effective CDK4/6 protein degraders. Among the newly synthesized compounds, 7f achieved dual degradation of CDK4/6 protein, with DC50 values of 10.5 and 2.5 nM, respectively. Compound 7f also exhibited inhibitory proliferative activity against Jurkat cells with an IC50 value of 0.18 μM. Furthermore, 7f induced cell apoptosis and G1 phase cell cycle arrest in a dose-dependent manner in Jurkat cells. In conclusion, these findings demonstrate the potential of 7f as a CDK4/6 degrader and a potential therapeutic strategy against cancer, thereby expanding the potential of CDK4/6 dual PROTACs.
摘要：
靶蛋白的降解被认为是一种有前途的治疗方法。但是合理设计用于降解的化合物仍然是一个挑战。在这项研究中,我们合理地设计和合成了10个化合物来发现有效的CDK4/6蛋白降解剂。在新合成的化合物中，7f取得了CDK4/6卵白的双重降解，DC50值为10.5和2.5nM，分别。化合物7f还表现出对Jurkat细胞的抑制增殖活性,IC50值为0.18μM。此外，7f在Jurkat细胞中以剂量依赖性方式诱导细胞凋亡和G1期细胞周期停滞。总之,这些发现证明了7f作为CDK4/6降解剂的潜力和潜在的癌症治疗策略，从而扩大了CDK4/6双PROTACs的潜力。
