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Property-Biased Covalent DNA-Encoded Library Screening Enabled the Discovery of AM-8719, A Structurally Novel,
Slavko Rast1, Marie Morgan-Fisher1, Sarah D Blomquist1
1Amgen Research, Rønnegade 8, Copenhagen2100, Denmark.
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.
Insights
Researchers discovered new KRAS G12C inhibitors that can enter the brain. These novel compounds show improved brain exposure and potency for treating KRAS-mutant lung cancer with brain metastases.
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.
