Discovery of AZD4747, a Potent and Selective Inhibitor of Mutant GTPase KRASG12C with Demonstrable CNS Penetration

Jason G. Kettle, Sharan K. Bagal, Derek Barratt, Michael S. Bodnarchuk, Scott Boyd, Erin Braybrooke, Jason Breed, Doyle J. Cassar, Sabina Cosulich, Michael Davies, Nichola L. Davies, Chao Deng, Andrew Eatherton, Laura Evans, Lyman J. Feron, Shaun Fillery, Emma S. Gleave, Frederick W. Goldberg, Miguel A. Cortés González, Carine Guerot, Afreen Haider, Stephanie Harlfinger, Rachel Howells, Anne Jackson, Peter Johnström, Paul D. Kemmitt, Alex Koers, Mikhail Kondrashov, Gillian M. Lamont, Scott Lamont, Hilary J. Lewis, Libin Liu, Megan Mylrea, Samuel Nash, Michael J. Niedbala, Alison Peter, Christopher Phillips, Kurt Pike, Piotr Raubo, Graeme R. Robb, Sarah Ross, Matthew G. Sanders, Magnus Schou, Iain Simpson, and Oliver Steward

Journal of Medicinal Chemistry 2023 66 (13), 9147-9160

DOI: 10.1021/acs.jmedchem.3c00746

The glycine to cysteine mutation at codon 12 of Kirsten rat sarcoma (KRAS) represents an Achilles heel that has now rendered this important GTPase druggable. Herein, we report our structure-based drug design approach that led to the identification of 14, AZD4747, a clinical development candidate for the treatment of KRASG12C-positive tumors, including the treatment of central nervous system (CNS) metastases. Building on our earlier discovery of C5-tethered quinazoline AZD4625, excision of a usually critical pyrimidine ring yielded a weak but brain-penetrant start point which was optimized for potency and DMPK. Key design principles and measured parameters that give high confidence in CNS exposure are discussed. During optimization, divergence between rodent and non-rodent species was observed in CNS exposure, with primate PET studies ultimately giving high confidence in the expected translation to patients. AZD4747 is a highly potent and selective inhibitor of KRASG12C with an anticipated low clearance and high oral bioavailability profile in humans.