Department of Chemical and Systems Biology, Chem-H, and Stanford Cancer Institute, Stanford School of Medicine, Stanford University, Stanford, CA, 94305, USA.
Department of Cancer Biology, Dana-Farber Cancer Institute, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, 02115, USA.
Eur J Med Chem. 2024 Oct 5;276:116613. doi: 10.1016/j.ejmech.2024.116613. Epub 2024 Jun 27.
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 CRL2 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.
细胞周期蛋白依赖性激酶 7 与细胞周期蛋白 H 和 MAT1 形成细胞周期蛋白依赖性激酶激活复合物 (CAK)，通过细胞周期 CDKs 的 T 环磷酸化来指导细胞周期进程。细胞周期蛋白依赖性激酶 7 的药理学抑制在细胞和体内模型中导致了选择性的抗癌作用，这促使了对该靶点的几项正在进行的临床研究。目前的细胞周期蛋白依赖性激酶 7 抑制剂要么是其催化活性的可逆抑制剂，要么是共价抑制剂。我们假设小分子靶向蛋白降解 (TPD) 可能会由于支架功能的丧失而导致不同的药理学。在这里，我们报告了一种强效细胞周期蛋白依赖性激酶 7 降解剂的设计和表征，该降解剂由与 CRL2 招募剂相连的 ATP 竞争性细胞周期蛋白依赖性激酶 7 结合物组成。JWZ-5-13 有效地在多种癌细胞中降解了细胞周期蛋白 7，并导致细胞增殖的强烈抑制。此外，化合物 JWZ-5-13 在在小鼠中进行的药代动力学研究中显示出了生物利用度。因此，JWZ-5-13 是一种有用的化学探针，可以研究细胞周期蛋白 7 降解的药理学后果。
