Slavko Rast, Marie Morgan-Fisher, Sarah D Blomquist, Jorge Peiró Cadahía, Sanne Cowland, Thomas Franch, Emil Glibstrup, Alex Gouliaev, Margit Haahr Hansen, Aleksejs Kontijevskis, Titi Kronborg, Loris Moretti, Anna Nadali, Søren Nielsen, Sebastian Leth-Petersen, Michael Rabe, Adili Alafate, Jennifer R Allen, Abhisek Banerjee, Shon K Booker, John R Butler, Imelda Hot, David Huang, Matthew R Kaller, Rajiv Kapoor, Qingyian Liu, Patricia Lopez, Vu Ma, Francesco Manoni, Jose M Medina, Alexander J Pickrell, Hui-Ling Wang, Jingjing Xie, Wenhan Zhang, Christopher Mohr, Kui Chen, Anne Y Saiki, Paul Wang, Monica Leavitt, Karen Rex, Guo Zhong, Ling Zou, Julie Lade, Upendra P Dahal, Nashid Farhan, Prashant Agarwal, Borna Zandkarimi, Kai Zhu, Gitte Husemoen, Nuria A Tamayo, Brian A Lanman
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.