Property-Biased Covalent DNA-Encoded Library Screening Enabled the Discovery of AM-8719, A Structurally Novel,...

Area of Science:

• Oncology
• Medicinal Chemistry
• Pharmacology

Background:

• Activating KRAS mutations drive nonsmall cell lung cancer (NSCLC) and often lead to central nervous system (CNS) metastases.
• Approved KRAS G12C inhibitors have shown CNS activity but possess low preclinical brain penetration, suggesting a need for agents with higher brain-to-plasma ratios.

Purpose of the Study:

• To apply DNA-encoded library (DEL) screening for identifying CNS-penetrant covalent KRAS G12C inhibitors.
• To discover novel inhibitors with enhanced CNS exposure and potency for treating KRAS-mutant NSCLC with brain metastases.

Main Methods:

• Utilized a property-biased covalent DEL-screening approach to identify initial hits.
• Employed structure-based design to optimize the hit series.
• Developed lead compound AM-8719 with improved potency and CNS penetration.

Main Results:

• Successfully identified a novel series of hydrogen bond donor-free KRAS G12C inhibitors using DEL screening.
• Achieved significantly improved CNS exposure in the discovered compounds.
• Delivered lead compound AM-8719, demonstrating 200-fold increased potency compared to initial hits and oral efficacy.

Conclusions:

• DNA-encoded library technology is effective for discovering CNS-penetrant covalent KRAS G12C inhibitors.
• The novel inhibitors, exemplified by AM-8719, offer potential for improved treatment of NSCLC with CNS metastases.
• Enhanced brain penetration and potency are key for developing effective therapies against KRAS-mutant lung cancer brain metastases.