Property-BiasedCovalent DNA-Encoded Library ScreeningEnabled the Discovery of AM-8719, A Structurally Novel, CNS-PenetrantKRAS G12C Inhibitor

Abstract Activating mutations in the Kirsten rat sarcoma (KRAS) gene are prevalent oncogenic drivers in nonsmall cell lung cancer (NSCLC). Patients harboring KRAS-mutant lung cancers frequently develop central nervous system (CNS) metastases. Although approved KRAS G12C inhibitors (i.e., sotorasib and adagrasib) show promising clinical CNS activity, these agents demonstrate low preclinical brain-to-plasma ratios, raising the question of whether compounds with elevated preclinical Kp,uu,brain values might show enhanced clinical performance. Here, we report the first successful application of DNA-encoded library (DEL) screening technology to the identification of CNS-penetrant covalent inhibitors of KRAS G12C. In this effort, a property-biased covalent DEL-screening approach enabled the discovery of a structurally novel series of hydrogen bond donor-free KRAS G12C inhibitors with improved CNS exposure. Leveraging structure-based design, we refined this hit series to deliver lead compound AM-8719, a CNS-penetrant, orally efficacious KRAS G12C inhibitor exhibiting 200-fold improved potency with respect to initial screening hits.