ALK5-IN-79 (compound 57), an ALK inhibitor, exhibits anticancer activity by inhibiting the TGF-β1/SMAD signaling pathway. It effectively reduces the production of extracellular matrix (ECM) and collagen deposition. Moreover, ALK5-IN-79 demonstrates satisfactory pharmacokinetic (PK) properties and favorable in vivo tolerance.

ALK5-IN-79, at a concentration of 1000 nM for 2 hours, exhibits moderate to strong inhibitory activity against ALK5, SRC, LCK, BRAF (V600E), ET, PDGFRα, EGFR, and KDR, with inhibition rates exceeding 20% [1]. At varying concentrations (0, 0.125, 0.25, 0.5, 1.0, and 2.0 μM) over a 1-hour period, ALK5-IN-79 inhibits the phosphorylation of smad3 in a dose-dependent manner [1]. Western Blot Analysis [1], using abnormally proliferating cancer-associated fibroblasts at concentrations ranging from 0 to 2.0 μM and a 1-hour incubation, demonstrates that ALK5-IN-79 blocks the upregulation of mRNA and protein levels of collagen I (Col1) and α-SMA, target genes of smad3, induced by TGF-β1. The compound also leads to a reduction in the secretion of Col1.

ALK5-IN-79, administered at 300 mg/kg via intraperitoneal injection daily for 7 days, did not lead to significant weight loss in mice, indicating safety for in vivo studies [1]. In the Pan02 syngeneic model, ALK5-IN-79 demonstrated tumor growth inhibition rates of 61.9% and 80.5% with doses of 10 mg/kg and 50 mg/kg, respectively, administered intravenously every other day for 24 days. In the PANC-1 subcutaneous xenograft model, the same dosing regimen resulted in tumor growth inhibition rates of 62.1% and 75.6%. Overall, ALK5-IN-79 effectively suppressed pancreatic cancer tumor growth in a dose-dependent manner [1].