Ras farnesylation as a target for novel antitumor agents: Potent and selective farnesyl diphosphate analog inhibitors of farnesyltransferase

Abstract

Protein prenylation is increasingly recognized as an important mechanism by which functional association of proteins t o membranes is mediated. Ras proteins, regulators of cell proliferation and differentiation, are among the proteins that undergo farnesylation, one of the two prenylation modifications known. Since ras proteins are activated into hyperactive oncogenic versions in a wide variety of human cancers, agents that d o w n modulate ras activity could be antineoplastic. Therefore, inhibitors of farnesyltransferase have the potential t o be of therapeutic value as anticancer agents due t o their ability t o block ras processing and hence its function. W e describe the identification of two farnesyl pyrophosphate (FPP) analogs that are potent and selective inhibitors of farnesyltransferase. While showing n o toxicity t o untransformed cells, a pivaloyloxyrnethyl ester of one of these inhibitors blocked ras mediated transformation of NIH 3T3 cells. In addition, both the ester and its parent acid inhibited ras farnesylation as measured by incorporation of labeled mevalonate into ras proteins in whole cells. Thus, this i s the first report of an FPP analog t o show biological activity by inhibiting ras processing i n whole cells. (0 1995 Wile"-Liss, Inc.

Crystallographic Analysis of CaaX Prenyltransferases Complexed with Substrates Defines Rules of Protein Substrate Selectivity

“…18,20 The eight cognate and cross-reactive peptide substrates presented here bind with the Ca 1 a 2 X motif inserted into the peptide-binding site, and bind without altering the enzyme or isoprenoid diphosphate structure, consistent with previous structures with bound substrates, products and inhibitors. [17][18][19][20][21][22][23][24][25][26][27][28][29] The Ca 1 a 2 X motif of the non-substrate Rap2b does not adopt an ordered conformation within the FTase active site, consistent with the observation that this peptide is a very poor FTase substrate.…”

Role of inhibitors of isoprenylation in proliferation, phenotype and apoptosis of human retinal pigment epithelium

“…MaA is a natural farnesyl pyrophosphate analog and acts as a potent, selective and competitive inhibitor of Ftase [18]. iFTIII was designed and synthesized as a farnesyl pyrophosphate analog [31]. It has a potent and selective activity in FTase inhibition.…”

Short-Term Local Delivery of an Inhibitor of Ras Farnesyltransferase Prevents Neointima Formation In Vivo After Porcine Coronary Balloon Angioplasty

“…FTase inhibitors may have an advantage over existing specific gene-targeting therapies or antisense oligonucleotide therapies, because they can target both Rasand Rho-dependent signaling. 10 In this article, we focused on whether the FTase inhibitor {(E,E)-2-[2-oxo-2-[(3,7,11-trimethyl-2,6,10-dodecatrienyl)oxy]aminoethyl] phosphonic acid, (2,2-dimethyl-1-oxopropoxy) methyl ester sodium} (farnesyl protein transferase inhibitor III, FPTIII) 11 acts on Ras-dependent activation of p42/p44 MAPK and blocks smooth muscle proliferation. These experiments enabled us to establish an effective concentration of FPTIII for subsequent local delivery after angioplasty in vivo to determine its effects on neointima formation and vascular function.…”