Development of Alectinib-Based PROTACs as Novel Potent Degraders of Anaplastic Lymphoma Kinase (ALK)

A series
of novel anaplastic lymphoma kinase (ALK) degraders were
designed and synthesized based on proteolysis-targeting chimera (PROTAC)
technology by linking two alectinib analogs (36 and 37) with pomalidomide through linkers of different lengths
and types. The most promising degrader 17 possessed a
high ALK-binding affinity and potent antiproliferative activity in
the ALK-dependent cell lines and did not exhibit obvious cytotoxicity
in ALK fusion-negative cells. More importantly, the efficacy of compound 17 in a Karpas 299 xenograft mouse model was further evaluated
based on its ALK-sustained degradation ability in vivo. The reduction in tumor weight in the compound 17-treated
group (10 mg/kg/day, I.V.) reached 75.82%, while alectinib reduced
tumor weight by 63.82% at a dose of 20 mg/kg/day (P.O.). Taken together,
our findings suggest that alectinib-based PROTACs associated with
the degradation of ALK may have promising beneficial effects for treating
ALK-driven malignancies.