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.

Automated summary

The development of a rationally designed covalent inhibitor, Con B-1, shows promising potential in selectively targeting ALK with low toxicity to normal cells. Compared to Ceritinib, Con B-1 demonstrates improved anticancer activities and potential antidrug resistant capabilities, making it a promising drug candidate for the treatment of NSCLC. This work provides a new perspective on the design of covalent inhibitors.