Discovery of LL-K8-22: A Selective, Durable, and Small-Molecule Degrader of the CDK8-Cyclin C Complex,Journal of Medicinal Chemistry

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Discovery of LL-K8-22: A Selective, Durable, and Small-Molecule Degrader of the CDK8-Cyclin C Complex
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2023-03-17 , DOI: 10.1021/acs.jmedchem.2c02045
Mingyu Wang _{1,

2} , Rongkun Lin ₃ , Jiacheng Li _{1,

2} , Yuying Suo _{1,

2} , Jing Gao ₄ , Liping Liu _{1,

2} , Liyuan Zhou ₅ , Yicheng Ni ₅ , Ziqun Yang _{2,

6} , Jie Zheng _{2,

6} , Jin Lin ₃ , Hu Zhou _{1,

2} , Cheng Luo _{1,

2,

3,

5,

7} , Hua Lin ₄

Affiliation

The CDK8–cyclin C complex is an important anti-tumor target, but unlike CDK8, cyclin C remains undruggable. Modulators regulating cyclin C activity directly are still under development. Here, a series of hydrophobic tagging-based degraders of the CDK8–cyclin C complex were designed, synthesized, and evaluated to identify the first dual degrader, LL-K8-22, which induced selective and synchronous degradation of CDK8 and cyclin C. Proteomic and immunoblot studies exhibited that LL-K8-22 significantly degraded CDK8 without reducing CDK19 and did not degrade other cyclin proteins except cyclin C. Moreover, LL-K8-22 showed enhanced anti-proliferative effects over its parental molecule, BI-1347, with potency increased by 5-fold in MDA-MB-468 cells. LL-K8-22 exhibited more pronounced effects on CDK8–cyclin C downstream signaling than BI-1347, suppressing STAT1 phosphorylation more persistently. RNA-sequencing analysis revealed that LL-K8-22 inhibited E2F- and MYC-driven carcinogenic transcriptional programs. Overall, LL-K8-22 is the first-in-class degrader of cyclin C and would be useful for studying the unknown functions of cyclin C.

中文翻译：

LL-K8-22 的发现：CDK8-细胞周期蛋白 C 复合物的选择性、持久性小分子降解剂

CDK8-细胞周期蛋白 C 复合物是重要的抗肿瘤靶点，但与 CDK8 不同，细胞周期蛋白 C 仍然不可成药。直接调节细胞周期蛋白 C 活性的调节剂仍在开发中。在这里，设计、合成和评估了一系列基于疏水标记的 CDK8-细胞周期蛋白 C 复合物降解剂，以确定第一个双降解剂LL-K8-22 ，它诱导 CDK8 和细胞周期蛋白 C 的选择性和同步降解。免疫印迹研究表明， LL-K8-22显着降解 CDK8，而不降低 CDK19，并且不降解除细胞周期蛋白 C 之外的其他细胞周期蛋白。此外， LL-K8-22比其亲本分子BI-1347表现出增强的抗增殖作用， MDA-MB-468 细胞中的效力增加了 5 倍。 LL-K8-22对 CDK8-细胞周期蛋白 C 下游信号传导的影响比BI-1347更显着，更持久地抑制 STAT1 磷酸化。 RNA 测序分析表明， LL-K8-22抑制 E2F 和 MYC 驱动的致癌转录程序。总体而言， LL-K8-22是同类首创的 cyclin C 降解剂，可用于研究 cyclin C 的未知功能。

更新日期：2023-03-17

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