Discovery of imidazo[1,2-b]pyridazine macrocyclic derivatives as novel ALK inhibitors capable of combating multiple resistant mutants

Anaplastic lymphoma kinase (ALK)-tyrosine kinase inhibitor (TKI) often loses effectiveness against non-small cell lung malignancies (NSCLCs) with ALK gene rearrangements (ALK⁺). 19 novel imidazo[1,2-b]pyridazine macrocyclic derivatives were designed, synthesized, and tested for their biological activities in an effort to develop ALK inhibitors that would overcome second-generation ALK-TKIs, particularly the G1202R mutation and the lorlatinib-resistant L1196M/G1202R double mutations. Of all the target substances, O-10 had the most effective enzymatic inhibitory activity, with IC₅₀ values for ALK^WT, ALK^G1202R, and ALK^{L1196M/G1202R} of 2.6, 6.4, and 23 nM, respectively. O-10, on the Other hand, reduced the growth of ALK-positive Karpas299, BaF3-EML4-ALK^G1202R, and BaF3-EML4-ALK^{L1196M/G1202R} cells with IC₅₀ values of 38, 52, and 64 nM, respectively. This was equally effective to the reference drug Repotrectinib (IC₅₀ = 40, 164, and 208 nM). The kinase selectivity profile, liver microsome stability test and in vivo pharmacokinetic properties in SD rats of compound O-10 were further evaluated. O-10 was regarded as an effective ALK inhibitor for the treatment of mutations overall.

Anaplastic lymphoma kinase inhibitors; Biological evaluations; G1202R mutant; Imidazo[1,2-b]pyridazine macrocyclic; L1196M/G1202R double mutations.