Identification and characterization of a terphenyl derivative blocking the G1-S transition in neoplastic cells

Over the past years, we have been engaged in a project aimed at the discovery of either innovative antitumor lead candidates or chemical tools able to modulate specific molecular pathways of neoplastic cells. Thus, taking advantage of a parallel approach, we synthesized a small library of organic molecules containing the stilbene privileged structure or derived from it. We evaluated the antiproliferative and proapoptotic activities of all the compounds, as well as the effects on the cell cycle of some representative ones. After further investigations, a terphenyl derivative (TR14) showed the most interesting biological profile, being able to interfere with the cell cycle progression at the G1-S transition by blocking the phosphorylation of Rb and inducing cell differentiation in K562 cells. Considering that the G1/S checkpoint is controlled by the phosphorylation of Rb, in turn carried out by Cdk4-6/cyclin D and Cdk2/cyclin E, we then examined the effects of TR14 on the expression of these proteins. The results of these experiments will provide hints as to the molecular target of TR14. Methodologically, they will also allow us to validate a chemical biological “top-down” protocol to the identification of both new biologically active compounds and their targets.