Discovery of macrocyclic CDK2/4/6 inhibitors with improved potency and DMPK properties through a highly efficient macrocyclic drug design platform.

[Display omitted] • An efficient macrocyclization platform was developed. • The workflow and potential of the macrocyclization platform was showed and demonstrated by its usage in the design of macrocyclic inhibitors of CDK2/4/6 from acyclic precursor NUV422. • The first molecule derived from the platform showed moderate to good inhibitory activity. • Further preliminary structure-activity relationship exploration led to compound 8 as a promising lead compound with better potency and drug-like properties. Cyclin-dependent kinases (CDKs) are critical cell cycle regulators that are often overexpressed in tumors, making them promising targets for anti-cancer therapies. Despite substantial advancements in optimizing the selectivity and drug-like properties of CDK inhibitors, safety of multi-target inhibitors remains a significant challenge. Macrocyclization is a promising drug discovery strategy to improve the pharmacological properties of existing compounds. Here we report the development of a macrocyclization platform that enabled the highly efficient discovery of a novel, macrocyclic CDK2/4/6 inhibitor from an acyclic precursor (NUV422). Using dihedral angle scan and structure-based, computer-aided drug design to select an optimal ring-closing site and linker length for the macrocycle, we identified compound 8 as a potent new CDK2/4/6 inhibitor with optimized cellular potency and safety profile compared to NUV422. Our platform leverages both experimentally-solved as well as generative chemistry-derived macrocyclic structures and can be deployed to streamline the design of macrocyclic new drugs from acyclic starting compounds, yielding macrocyclic compounds with enhanced potency and improved drug-like properties. [ABSTRACT FROM AUTHOR]