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

Journal of Medicinal Chemistry

DOI: 10.1021/acs.jmedchem.6c01357

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.