Discovery of bivalent small molecule degraders of cyclin-dependent kinase 7 (CDK7)

Le résumé fourni par la source

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 VHL 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. A potent and selective CDK7 degrader was developed. JWZ-5-13 induces a rapid and sustained CDK7 degradation and exhibits high proteome-wide selectivity. JWZ-5-13 displays advantages in inhibition of cancer cell proliferation over its parental binder and displays bioavailability in a pharmacokinetic study. • JWZ-5-13 significantly degrades CDK7 in low nanomolar in multiple cell line. • JWZ-5-13 exhibits high proteome-wide selectivity. • JWZ-5-13 exhibited advantages in inhibition of cancer cell proliferation over its parental binder. • JWZ-5-13 displayed bioavailability in a pharmacokinetic study.

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