Aiming to track the potential antitumor effect of novel allosteric autotaxin (ATX) inhibitors, a hybrid strategy was utilized by merging ATX inhibitors PF-8380 and GLPG1690, while the piperazinyl group in GLPG1690 was replaced with benzene ring to furnish imidazo[1,2-a]pyridine derivatives 10ã10k. Based on ATX enzymatic assay, we further changed the substituents within benzyl carbamate moiety and tuned the carbamate linker to urea group. Delightfully, compound 10c bearing a N-hydroxyethyl piperazinyl group was identified as the optimal ATX inhibitor with an IC50 value of 3.4 nM 10c exerted the most impressive antitumor effects, especially on Hep3B (0.58 μM) and RAW264.7 (0.63 μM) cell lines highly expressing ATX mRNA. Moreover, 10c could dose-dependently suppress the RAW264.7 cell migration rate in wound healing assay and significantly inhibit RAW264.7 cell colony formation. Meanwhile, 10c was capable of inducing weak to moderate apoptosis and achieved notable G2 phase arrest on RAW264.7 cells. Taken together, 10c may serve as a novel lead to probe possible role of ATX allosteric inhibitors in tumor diseases.
Keywords: ATX allosteric Inhibitors; Antitumor; Apoptosis & cell cycle arrest; Imidazo[1,2-a]pyridine; Structural evolution.
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