Synthesis and biological evaluation of novel benzo[c] [1,2,5]thiadiazol-5-yl and thieno [3,2-c] - pyridin-2-yl imidazole derivatives as ALK5 inhibitors

Transforming growth factor (TGF-beta), a key mediator of tumor growth and metastasis, has been recognized as an important cancer drug target. A series of benzo[c][1,2,5]thiadiazol-5-yl imidazoles (14a-g) and thieno [3,2-c]-pyridin-2-yl imidazoles (20a-g) were designed, synthesized, and evaluated for their activin receptor-like kinase 5 (ALK5) activities. Among these compounds, 14c showed the highest activity (IC50 = 0.008 mu M) against ALK5 kinase, which was 16.1-fold and 1.8-fold higher than those of positive control compounds LY-2157 299 (IC50 = 0.129 mu M) and EW-7 197 (IC50 = 0.014 mu M), respectively. Compound 14g (350) showed the highest selectivity index of ALK5 against p38 alpha MAP kinase, which was significantly higher than that of positive control compounds LY-2157 299 (4) and EW-7 197 (211). The inhibitory effects of compound 14c on TGF-beta-induced Smad signaling and cell motility were studied in SPC-A1, HepG2 and HUVEC cells using western blot analysis and wound healing assay. ADMET prediction analysis showed that compounds 14c and 14g had good pharmacokinetics and drug-likeness behaviors.