A covalent fragment-based strategy targeting a novel cysteine to inhibit activity of mutant EGFR kinase
Naoki Kuki, Lee Walmsley, Kazuo Kanai, Sho Takechi, Masao Yoshida, Ryo Murakami, Kohei Takano, Yuichi Tominaga, Mizuki Takahashi, Shuichiro Ito, Naoki Nakao, Hayley C. Angove, Lisa Baker, Edward Carter, P. Dokurno, Loic Le Strat, Alba T. Macias, Carrie-Anne Molyneaux, James B. Murray, A.E. Surgenor, Tomoaki Hamada, Roderick E. Hubbard
Abstract
for ATP. A third generation of drugs, such as osimertinib were developed which were effective against T790M EGFR in which an acrylamide moiety forms a covalent bond with C797, although resistance has emerged by mutation to S797. A fragment-based screen to identify new starting points for an EGFR inhibitor serendipitously identified a fragment that reacted with C775, a previously unexploited residue in the ATP binding pocket for a covalent inhibitor to target. A number of acrylamide containing fragments were identified that selectively reacted with C775. One of these acrylamides was optimized to a highly selective inhibitor with sub-1 μM activity, that is active against T790M, C797S mutant EGFR independent of ATP concentration, providing a potential new strategy for pan-EGFR mutant inhibition.