XR-3054

In this report, a novel inhibitor of farnesyl protein transferase (FPTase) is described. The compound, XR3054, is structurally similar to farnesol, a component of the reaction in which FPTase catalyses transfer of farnesol pyrophosphate to the CAAX recognition motif on proteins. The compound was selected initially because of its ability to inhibit in vitro farnesylation of CAAX recognition peptides with an IC50 of 50 microM. The farnesylation of p21 ras was reduced in a dose-dependent manner in the presence of XR3054. Similarly XR3054 was able to reduce the anchorage-independent growth of V12 H-ras transformed NIH 3T3 cells in a focus formation assay in soft agar, with an IC50 value of 30 microM, whilst not affecting the anchorage-independent growth of v-raf transformed cells. XR3054 reduced the phosphorylation of p42 mitogen activated protein (MAP) kinase in parental NIH 3T3 cells and V12 H-ras transformed NIH 3T3 cells, but constitutively active v-raf transformed cells showed no reduction in phosphorylation of ERK2 in the presence of XR3054. XR3054 inhibited the proliferation of the prostatic cancer cell lines LnCAP and PC3 and the colon carcinoma SW480 and HT1080 (IC50 values of 12.4, 12.2, 21.4 and 8.8 microM, respectively) but was relatively inactive when tested against a panel of breast carcinoma cell lines. The activity did not relate to the presence of mutant or wild-type ras in the cell lines tested. In conclusion XR3054 inhibits ras farnesylation, MAP kinase activation and anchorage-independent growth in NIH 3T3 transformed with v12 H-ras. Since the antiproliferative effect of the compound is not related to the ras phenotype, XR3054 may also have effects on other cell signalling mechanisms.