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

Area of Science:

• Medicinal Chemistry
• Oncology
• Drug Discovery

Background:

• Covalent inhibition of KRAS G12C is a key strategy for non-small cell lung cancer (NSCLC).
• Traditional screening methods for KRAS G12C inhibitors are limited by library size and diversity.
• DNA-encoded library (DEL) technology offers a powerful platform for screening vast chemical spaces.

Purpose of the Study:

• To design and synthesize a covalent DEL for screening against KRAS G12C.
• To identify novel, potent, and selective covalent KRAS G12C inhibitors.
• To evaluate the pharmacokinetic and pharmacodynamic properties of identified inhibitors.

Main Methods:

• Development of a covalent DNA-encoded library.
• Screening of approximately 16 million compounds against KRAS G12C.
• Hit identification, validation, and structure-based optimization.
• In vitro and in vivo evaluation of inhibitor efficacy.

Main Results:

• Successful design and synthesis of a covalent DEL.
• Identification of a series of structurally novel covalent KRAS G12C inhibitors.
• Demonstration of potent and selective inhibition of KRAS G12C.
• Favorable pharmacokinetic profiles and promising in vivo pharmacodynamic effects.

Conclusions:

• Covalent DEL screening is an effective strategy for discovering novel KRAS G12C inhibitors.
• The identified inhibitors represent promising candidates for NSCLC treatment.
• This approach accelerates the development of targeted cancer therapies.