Development of Dual and Selective Degraders of Cyclin-Dependent Kinases 4 and 6.
Development of Dual and Selective Degraders of Cyclin-Dependent Kinases 4 and 6.
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DOI：
10.1002/anie.201901336
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发表时间：
2019-05-06
期刊：
影响因子：
--
通讯作者：
Gray NS
中科院分区：
文献类型：
--
作者：
Jiang B;Wang ES;Donovan KA;Liang Y;Fischer ES;Zhang T;Gray NS
细胞周期蛋白依赖性激酶4和6（CDK 4/6）是细胞周期的关键调节因子，CDK 4/6抑制剂被FDA批准用于治疗转移性乳腺癌患者。然而，由于其ATP结合位点的保守性，选择性试剂的开发仍然难以捉摸。在这里，我们报告了能够降解CDK 4/6或选择性降解CDK 4或CDK 6的基于酰亚胺的降解剂分子。我们还能够调整这些分子对Ikaros（IKZF 1）和Aiolos（IKZF 3）的活性，这是基于酰亚胺的降解剂的公认靶标。我们发现，在套细胞淋巴瘤细胞系中，与CDK 4/6抑制、CDK 4/6降解或IKZF 1/3降解相比，IKZF 1/3降解与CDK 4/6双重降解的组合表现出增强的抗增殖作用。总之，我们在这里报告的第一个化合物能够诱导CDK 4和CDK 6的选择性降解的工具，以解剖其不同的生物功能。
Cyclin-dependent kinases 4 and 6 (CDK4/6) are key regulators of the cell cycle, and CDK4/6 inhibitors are FDA-approved for treating patients with metastatic breast cancer. However, due to conservation of their ATP-binding sites, development of selective agents has remained elusive. Here, we report imide-based degrader molecules capable of degrading both CDK4/6, or selectively degrading either CDK4 or CDK6. We were also able to tune the activity of these molecules against Ikaros (IKZF1) and Aiolos (IKZF3), well-established targets of imide-based degraders. We found that in mantle cell lymphoma cell lines, combined IKZF1/3 degradation with dual CDK4/6 degradation exhibited enhanced anti-proliferative effects compared to CDK4/6 inhibition, CDK4/6 degradation, or IKZF1/3 degradation. In sum, we report here the first compounds capable of inducing selective degradation of CDK4 and CDK6 as tools to pharmacologically dissect their distinct biological functions.
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影响因子：
14.8
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