Targeting Cysteine Located Outside the Active Site: An Effective Strategy for Covalent ALKi Design

Potent
inhibitors of ALK are highly desired because of the occurrence
of drug resistance. We herein firstly report the development of a
rationally designed inhibitor, Con B-1, which can covalently
bind to Cys1259, a cysteine located outside the ALK active site by
linking a warhead with Ceritinib through a 2,2′-Oxybis­(ethylamine)
linker. The in vitro and in vivo assays showed ConB-1 is a potent selective ALKi with
low toxicity to normal cells. In addition, the molecule showed significant
improvement of anticancer activities and potential antidrug resistant
activity compared with Ceritinib, demonstrating the covalent inhibitor
of ALK can be a promising drug candidate for the treatment of NSCLC.
This work may provide a novel perspective on the design of covalent
inhibitors.