Identification of Structurally Novel KRAS^G12C Inhibitors through Covalent DNA-Encoded Library Screening.

ABSTRACT: Covalent inhibition of the KRAS^G12C oncoprotein has emerged as a promising therapeutic approach for the treatment of nonsmall cell lung cancer (NSCLC). The identification of KRAS^G12C inhibitors has typically relied on the high-throughput screening (HTS) of libraries of cysteine-reactive small molecules or on the attachment of cysteine-reactive warheads to noncovalent binders of KRAS. Such screening approaches have historically been limited in the size and diversity of molecules that could be effectively screened. DNA-encoded library (DEL) screening has emerged as a promising approach to accelerate the preparation and screening of incredibly large and diverse chemical libraries. Here, we describe the design and synthesis of a covalent DEL to screen ∼16 million compound

SUBMITTER: Huang D 

PROVIDER: S-EPMC11873997 | biostudies-literature | 2025 Feb

REPOSITORIES: biostudies-literature