MOE Key Laboratory of Protein Sciences, School of Pharmaceutical Sciences, MOE Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Tsinghua University, Beijing, China.
Institute of Pharmacology and Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
Nat Chem Biol. 2021 May;17(5):567-575. doi: 10.1038/s41589-021-00742-5. Epub 2021 Mar 4.
The discovery of effective therapeutic treatments for cancer via cell differentiation instead of antiproliferation remains a great challenge. Cyclin-dependent kinase 2 (CDK2) inactivation, which overcomes the differentiation arrest of acute myeloid leukemia (AML) cells, may be a promising method for AML treatment. However, there is no available selective CDK2 inhibitor. More importantly, the inhibition of only the enzymatic function of CDK2 would be insufficient to promote notable AML differentiation. To further validate the role and druggability of CDK2 involved in AML differentiation, a suitable chemical tool is needed. Therefore, we developed first-in-class CDK2-targeted proteolysis-targeting chimeras (PROTACs), which promoted rapid and potent CDK2 degradation in different cell lines without comparable degradation of other targets, and induced remarkable differentiation of AML cell lines and primary patient cells. These data clearly demonstrated the practicality and importance of PROTACs as alternative tools for verifying CDK2 protein functions.
通过细胞分化而不是抗增殖来发现有效的癌症治疗方法仍然是一个巨大的挑战。细胞周期蛋白依赖性激酶 2（CDK2）失活可以克服急性髓系白血病（AML）细胞的分化阻滞，可能是治疗 AML 的一种有前途的方法。但是，目前尚无可用的选择性 CDK2 抑制剂。更重要的是，仅抑制 CDK2 的酶功能不足以促进明显的 AML 分化。为了进一步验证 CDK2 在 AML 分化中的作用和可药性，需要合适的化学工具。因此，我们开发了首创的 CDK2 靶向蛋白水解靶向嵌合体（PROTACs），这些嵌合体在不同的细胞系中可快速有效地降解 CDK2，而对其他靶标没有可比的降解作用，并诱导 AML 细胞系和原代患者细胞的显著分化。这些数据清楚地表明了 PROTAC 作为验证 CDK2 蛋白功能的替代工具的实用性和重要性。
