细胞周期蛋白依赖性激酶 7 与细胞周期蛋白 H 和 MAT1 一起形成 CDK 激活复合物 (CAK)，通过细胞周期 CDK 的 T 环磷酸化来指导细胞周期进程。 CDK7 的药理学抑制可在细胞和体内模型中产生选择性抗癌作用，从而激发了对该靶标正在进行的多项临床研究。目前的 CDK7 抑制剂是其催化活性的可逆抑制剂或共价抑制剂。我们假设小分子靶向蛋白降解（TPD）可能由于支架功能的丧失而导致药理学差异。在这里，我们报告了一种有效的 CDK7 降解剂的设计和表征，该降解剂由与 CRL2VHL 招募剂连接的 ATP 竞争性 CDK7 结合物组成。 JWZ-5-13 可有效降解多种癌细胞中的 CDK7，并有效抑制细胞增殖。此外，化合物 JWZ-5-13 在小鼠体内进行的药代动力学研究中显示出生物利用度。因此，JWZ-5-13 是一种有用的化学探针，可用于研究 CDK7 降解的药理学后果。版权所有 © 2024 Elsevier Masson SAS。版权所有。

Cyclin-dependent kinase 7, along with cyclin H and MAT1, forms the CDK-activating complex (CAK), which directs cell cycle progression via T-loop phosphorylation of cell cycle CDKs. Pharmacological inhibition of CDK7 leads to selective anti-cancer effects in cellular and in vivo models, motivating several ongoing clinical investigations of this target. Current CDK7 inhibitors are either reversible or covalent inhibitors of its catalytic activity. We hypothesized that small molecule targeted protein degradation (TPD) might result in differentiated pharmacology due to the loss of scaffolding functions. Here, we report the design and characterization of a potent CDK7 degrader that is comprised of an ATP-competitive CDK7 binder linked to a CRL2VHL recruiter. JWZ-5-13 effectively degrades CDK7 in multiple cancer cells and leads to a potent inhibition of cell proliferation. Additionally, compound JWZ-5-13 displayed bioavailability in a pharmacokinetic study conducted in mice. Therefore, JWZ-5-13 is a useful chemical probe to investigate the pharmacological consequences of CDK7 degradation.Copyright © 2024 Elsevier Masson SAS. All rights reserved.