Synthesis and evaluation of the epithelial-to- mesenchymal inhibitory activity of indazole-derived imidazoles as dual ALK5/p38α MAP inhibitors

Drugs of targeting both activin receptor-like kinase 5 (ALK5) and p38 alpha have therapeutic advantages, making them attractive treatment options for tumors. Two series of 4-(1H-indazol-5-yl)-5-(6-methylpyridin-2-yl)-1H-imidazoles 13a-g and 4-(1-methyl-1H-indazol-5-yl)-5-(6-methylpyridin-2-yl)1H-imidazoles 20a-g were synthesized and evaluated for ALK5 and p38 alpha mitogen-activated protein kinase inhibitory activity. The most potent compound, 13c (J-1090), inhibited ALK5- and p38 alpha-mediated phosphorylation with half-maximal inhibitor concentrations of 0.004 mM and 0.004 mM, respectively, in the enzymatic assay. In this study, the effectiveness of 13c in transforming growth factor (TGF-beta)-exposed U87MG cells was investigated using western blotting, immunofluorescence assays, cell migration assay, invasion assay, and RT-PCR analysis. 13c inhibited the protein expression of Slug and the protein and RNA expression of the mesenchymal-related proteins N-cadherin and vimentin. Furthermore, 13c markedly suppressed TGF-beta-induced epithelial-to-mesenchymal transition (EMT), migration, and invasion in U87MG cells. These results suggest that 13c is a novel inhibitor of ALK5 with potential utility in the treatment of human glioma. (C) 2021 Elsevier Masson SAS. All rights reserved.

Automated summary

Compounds targeting both ALK5 and p38α were synthesized and evaluated, with one compound, 13c, showing potential as an inhibitor in the treatment of human glioma.