Discovery of imidazo[1,2-b]pyridazine macrocyclic derivatives as novel ALK inhibitors capable of combating multiple resistant mutants.
Xiao X, Xu Y, Yu X, Chen Y, Zhao W, Xie Z, Zhu X, Xu H, Yang Y, Zhang P.
Anaplastic lymphoma kinase (ALK)-tyrosine kinase inhibitor (TKI) often loses effectiveness against non-small cell lung malignancies (NSCLCs) with ALK gene rearrangements (ALK<sup>+</sup>). 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 IC<sub>50</sub> values for ALK<sup>WT</sup>, ALK<sup>G1202R</sup>, and ALK<sup>L1196M/G1202R</sup> 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<sup>G1202R</sup>, and BaF3-EML4-ALK<sup>L1196M/G1202R</sup> cells with IC<sub>50</sub> values of 38, 52, and 64 nM, respectively. This was equally effective to the reference drug Repotrectinib (IC<sub>50</sub> = 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.