Novel triazole based inhibitors of Ras farnesyl transferase.

A novel series of potent inhibitors of Ras farnesyl transferase possessing a 1,2,4-triazole pharmacophore is described. These inhibitors were discovered from a parallel synthesis effort and were subsequently optimized to in vitro IC(50) value of less than 1nM.

The farnesyltransferase inhibitor R115777 reduces hypoxia and matrix metalloproteinase 2 expression in human glioma xenograft.

Purpose: The high-grade primary brain tumors, glioblastoma, of extremely bad prognosis contain large regions of hypoxia known to be involved in the chemo- and radioresistance. We demonstrated previously that radioresistant human wild-type Ras U87 glioblastoma can be radiosensitized in vitro by the specific farnesyltransferase inhibitor R115777. The aim of this study was to analyze the effect of this compound on the hypoxic status and the vascularization of this tumor.

Farnesyltransferase inhibitor, R115777, reverses the resistance of human glioma cell lines to ionizing radiation.

We investigated for the first time the ability of farnesyltransferase inhibitors (FTI) to radiosensitize human glioma. For this, human glioma cell lines were treated with the specific FTI, R115777, 48 hr prior to a 2Gy irradiation. The treatment with R115777 decreased by 45% the SF2 value of the more radioresistant glioma cell lines (SF763 and U87) without any significant effect on the radioresistance of the radiosensitive ones (SF767 and U251-MG).