Abstract
The stem cell factor receptor (cβKit) has been known to play critical roles in regulating numerous aspects of cellular behavior including cell growth, differentiation, migration and metabolism. In this investigation, a threeβdimensional pharmacophore model of cβKit inhibitors has been established by using the HypoGen algorithms implemented in the catalyst software package. The best quantitative pharmacophore model, hypothesis 1, which has the highest correlation coefficient (0.989), consists of one hydrogen bond acceptor, two hydrogen bond donors and one hydrophobic feature. To our knowledge, this is the first report on the pharmacophore modeling study of cβKit inhibitors. The best hypothesis, hypothesis 1, was used to screen molecular structural databases, including Specs and China Natural Products Database for potential lead compounds. The hit compounds were subsequently subjected to filtering by Lipinski's rules and docking study to refine the retrieved hits and as a result to reduce the rate of false positive. Finally 28 compounds were purchased or synthesized for further in vitro assay against several human tumour cell lines including A549, MCFβ7, HepG2 and PCβ3, in which cβKit is overexpressed. Two compounds show very low micromolar inhibition potency against the PCβ3 and HepG2 cell lines respectively. And they were selected for further modification and testing.