Jude Canon, Karen Rex, Anne Y Saiki, Christopher Mohr, Keegan Cooke, Dhanashri Bagal, Kevin Gaida, Tyler Holt, Charles G Knutson, Neelima Koppada, Brian A Lanman, Jonathan Werner, Aaron S Rapaport, Tisha San Miguel, Roberto Ortiz, Tao Osgood, Ji-Rong Sun, Xiaochun Zhu, John D McCarter, Laurie P Volak, Brett E Houk, Marwan G Fakih, Bert H O'Neil, Timothy J Price, Gerald S Falchook, Jayesh Desai, James Kuo, Ramaswamy Govindan, David S Hong, Wenjun Ouyang, Haby Henary, Tara Arvedson, Victor J Cee, J Russell Lipford
KRAS is the most frequently mutated oncogene in cancer and encodes a key signalling protein in tumours1,2 . The KRAS(G12C) mutant has a cysteine residue that has been exploited to design covalent inhibitors that have promising preclinical activity3-5 . Here we optimized a series of inhibitors, using novel binding interactions to markedly enhance their potency and selectivity. Our efforts have led to the discovery of AMG 510, which is, to our knowledge, the first KRAS(G12C) inhibitor in clinical development...
November 2019: Nature