Design,Synthesis And Anti-tumor Activity Of ALK5 Inhibitors Based On Chalcone Scaffold

It has demonstrated that TGF-?excessive expression can directly lead to the occurrence and deterioration of tumor and fibrotic diseases.Serine/threonine kinase ALK5 as the TGF-?type I receptor has been considered as a novel drug target to develop anti-tumor agents by many pharmaceutical companies.And some of ALK5 inhibitors are in clinical research.The preliminary results of computer-aided-drug-design research suggested that the chalcone analogues exhibited inhibitory activity on ALK5,so 16 derivatives based on chalcone scaffold have been designed and synthesized.The anti-tumor activity of title compounds has been screened in cancer cell lines,including the inhibitory effect on the ALK5 kinase.Next,the binding model and molecular dynamics simulation of complexes have been studied.In our initial work,11 compounds were screened from the compound database and then the results of ELISA test showed that chalcone analogs exhibited apparent inhibitory activity on ALK5.Hence,we designed and synthesized 16 derivatives of chalone.The cytotoxicity of compounds were screened in cancer cell A549,HeLa,HepG-2 and HL-60 by MTT method,showing the better inhibition activity on HeLa(the range of IC₅₀=1.76⁶7.71?M)than on other cells.Among the compound,a6(IC₅₀=1.76±2.33?M),a11(IC₅₀=2.00±0.56?M)and a13(IC₅₀=1.82±1.62?M)exhibited good inhibition activity compared with positive-control LY364947(IC₅₀=3.47±1.39?M).a14 showed the moderate cytotoxicity(IC₅₀=6.4±2.35?M).Besides,the compound a11,a14induced the apoptosis.The inhibition activity on ALK5 of selected compounds showed that compounds a4(IC₅₀=8.12?M),a6(IC₅₀=2.60?M),a11(IC₅₀=0.38?M)and a14(IC₅₀=0.68?M)exhibited better inhibition.The docking mode and molecular dynamics simulation showed that the target compounds could enter into the key cavity and form H-H bond and hydrophobic interaction with key residues.And the complex system could be stable in the simulated environment.We concluded that the research results on chalcone compounds are promising for the development of ALK5 inhibitors.