Abstract:Farnesyltransferase inhibitors (FTIs) represent a promising new approach for the treatment of cancer. Although the exact mechanism of action of these compounds is not fully understood, several compounds have progressed into clinical trials with proven efficacy. This review will describe the recent patents (2000 to present) that cover FTIs in the clinic, together with other classes that are still under development.
“…Hence, a set of alterations designed to increase in vivo drug stability and membrane permeation, without significantly compromising the effective inhibitory activity associated, have been attempted. A very large number of FTIs having a variety of amide bond replacements, and differing on the peptide conformation and degree of flexibility mimetized, on the size and hydrophobicity degree of the spacers used to link the terminal cysteine and methionine residues, and on the presence or absence of the carboxyl group, the methionine branch, or the cysteine thiol moiety have been reported [137][138][139][140][141][142][143][144]. L-731,734, BZA-5B, and B581 were among the first of these peptide analogues [145][146][147], but the number of CAAX mimics tested in FTase inhibition is extremely vast.…”
Section: Peptide Analoguesmentioning
confidence: 99%
“…However, very few information on the latter three drug candidates has been disclosed. The development of FTIs has been reviewed in several articles [5,19,92,137,141,142,[185][186][187][188]. A very good and detailed account on the clinical trials performed for FTIs as of 2003 is presented in [186].…”
Farnesyltransferase (FTase) is a zinc enzyme that has been the subject of particular attention in anti-cancer research. This enzyme promotes the addition of a farnesyl group from farnesyl diphosphate (FPP) to a cysteine residue of a protein substrate containing a typical -CAAX motif at the carboxyl terminus. Initial interest in FTase inhibition was prompted by the finding that farnesylation was absolutely required for the oncogenic forms of ras proteins to transform cells, as ras proteins have been implicated in around 30% of all human cancers. This discovery led to frenetic search for FTase inhibitors (FTIs), with more than 400 patents registered in less than a decade. However, despite the very promising initial results, the outcome of Phase II and Phase III clinical trials was, is general, rather disappointing, with the most advanced FTIs failing to demonstrate anti-tumor activity in ras dependent cancers, presumably because K-ras, the most frequently mutated form of ras in human cancers, is able to bypass FTI blockade through cross-prenylation by the related enzyme geranylgeranyltransferase I (GGTase I). Surprisingly, several of these compounds were later shown to have anti-tumor activity against non-ras dependent cancers, launching the grounds for a new and exciting era in FTIs research and development, although the precise target for the FTIs activity of these compounds still remains unknown. This review reports the recent progress in the field, presenting a comprehensive summary of the most promising FTIs, in terms of their chemical structure and properties, taking into account the topology of the enzyme's active-site, and the most recent mechanistic results on the catalytic activity of FTase, both at the theoretical and mechanistic level. These features are presented in close linking with the available results on the biological activity of these inhibitors, and with the outcome of the most recent clinical trials.
“…Hence, a set of alterations designed to increase in vivo drug stability and membrane permeation, without significantly compromising the effective inhibitory activity associated, have been attempted. A very large number of FTIs having a variety of amide bond replacements, and differing on the peptide conformation and degree of flexibility mimetized, on the size and hydrophobicity degree of the spacers used to link the terminal cysteine and methionine residues, and on the presence or absence of the carboxyl group, the methionine branch, or the cysteine thiol moiety have been reported [137][138][139][140][141][142][143][144]. L-731,734, BZA-5B, and B581 were among the first of these peptide analogues [145][146][147], but the number of CAAX mimics tested in FTase inhibition is extremely vast.…”
Section: Peptide Analoguesmentioning
confidence: 99%
“…However, very few information on the latter three drug candidates has been disclosed. The development of FTIs has been reviewed in several articles [5,19,92,137,141,142,[185][186][187][188]. A very good and detailed account on the clinical trials performed for FTIs as of 2003 is presented in [186].…”
Farnesyltransferase (FTase) is a zinc enzyme that has been the subject of particular attention in anti-cancer research. This enzyme promotes the addition of a farnesyl group from farnesyl diphosphate (FPP) to a cysteine residue of a protein substrate containing a typical -CAAX motif at the carboxyl terminus. Initial interest in FTase inhibition was prompted by the finding that farnesylation was absolutely required for the oncogenic forms of ras proteins to transform cells, as ras proteins have been implicated in around 30% of all human cancers. This discovery led to frenetic search for FTase inhibitors (FTIs), with more than 400 patents registered in less than a decade. However, despite the very promising initial results, the outcome of Phase II and Phase III clinical trials was, is general, rather disappointing, with the most advanced FTIs failing to demonstrate anti-tumor activity in ras dependent cancers, presumably because K-ras, the most frequently mutated form of ras in human cancers, is able to bypass FTI blockade through cross-prenylation by the related enzyme geranylgeranyltransferase I (GGTase I). Surprisingly, several of these compounds were later shown to have anti-tumor activity against non-ras dependent cancers, launching the grounds for a new and exciting era in FTIs research and development, although the precise target for the FTIs activity of these compounds still remains unknown. This review reports the recent progress in the field, presenting a comprehensive summary of the most promising FTIs, in terms of their chemical structure and properties, taking into account the topology of the enzyme's active-site, and the most recent mechanistic results on the catalytic activity of FTase, both at the theoretical and mechanistic level. These features are presented in close linking with the available results on the biological activity of these inhibitors, and with the outcome of the most recent clinical trials.
“…Interference of the association of these proteins to the plasma membrane through FTase inhibition nearly reduces or terminates the growth of cancer cells, which identifies farnesyltransferase as a viable therapeutic target ( − ). Several FTase inhibitors (FTIs) have entered different clinical trial phases along the drug discovery pipeline, showing promise in the clinical treatment of human cancers ( − ). 1 The farnesylation reaction.…”
Farnesyltransferase (FTase) catalyzes the transfer of farnesyl from farnesyl diphosphate (FPP) to cysteine residues at or near the C-terminus of protein acceptors with a CaaX motif (a, aliphatic; X, Met). Farnesylation is a critical modification to many switch proteins involved in the extracellular signal transduction pathway, which facilitates their fixation on the cell membrane where the extracellular signal is processed. The malfunction caused by mutations in these proteins often causes uncontrolled cell reproduction and leads to tumor formation. FTase inhibitors have been extensively studied as potential anticancer agents in recent years, several of which have advanced to different phases of clinical trials. However, the mechanism of this biologically important enzyme has not been firmly established. Understanding how FTase recruits the FPP substrate is the first and foremost step toward further mechanistic investigations and the design of effective FTase inhibitors. Molecular dynamic simulations were carried out on the ternary structure of FTase complexed with the FPP substrate and an acetyl-capped tetrapeptide (acetyl-CVIM), which revealed that the FPP substrate maintains an inactive conformation and the binding of the diphosphate group can be largely attributed to residues R291beta, K164alpha, K294beta, and H248beta. The FPP substrate assumes an extended conformation in the binding site with restricted rotation of the backbone dihedral angles; however, it does not have a well-defined conformation when unbound in solution. This is evident from multinanosecond MD simulations of the FPP substrate in a vacuum and solution. Our conclusion is further supported by theoretical J coupling calculations. Our results on the FPP binding are in good agreement with previous experimental kinetic studies on FTase mutants. The hypothetical conformational activation of the FPP substrate is currently under investigation.
“…8,9 Initial interest in FTase arose from the discovery that farnesylation is absolutely necessary for oncogenic forms of Ras proteins to transform cells; [10][11][12] Ras proteins have been implicated in around 30% of all human cancers. 13,14 Targeting FTase thus became for some years the Holy Grail of anticancer drug design and development, 15 with an absolute plethora of patents describing FTase inhibitors (FTIs) published 6 and several drugs moving into clinical testing. [16][17][18][19][20] Despite, the very promising initial results, the outcome of phase II and phase III clinical trials was rather disappointing, with the most advanced FTIs failing to demonstrate antitumor activity in Ras dependent cancers.…”
Section: Introductionmentioning
confidence: 99%
“…Farnesyltransferase (FTase) is a zinc enzyme that consists of a 48 kDa α-subunit and a 46 kDa β-subunit – and that has been the subject of particular interest in anticancer research over the past decade. – This enzyme promotes the addition of the isoprenoid farnesyl group from farnesyl diphosphate (FPP) to a cysteine residue of a protein substrate containing a typical CAAX motif at the carboxyl terminus, where C represents the cysteine residue that is farnesylated, A is an aliphatic amino acid, and X represents the terminal amino acid residue, usually alanine, serine, methionine, or glutamine . The list of known substrates of FTase comprises the H-, N-, and K-Ras proteins, nuclear lamins A and B, the γ subunit of heterotrimeric G-proteins, and several proteins involved in visual signal transduction. , …”
Farnesyltransferase enzyme (FTase) is an interesting target for anticancer therapy that has been the subject of particular attention over the past decade. However, despite of the thrilling achievements in the development of farnesyltransferase inhibitors (FTIs) over the past few years, the farnesylation mechanism remains, to some degree, a mystery. This work describes the application of molecular dynamics simulations to the study of enzyme flexibility in the 4 key intermediate states formed during the FTase catalytic mechanism--FTase resting state, binary complex (FTase-FPP), ternary complex (FTase-FPP-Peptide), and product complex (FTase-Product)--thereby covering the main states in the mechanistic pathway of this mysterious enzyme, while relating, dissecting, and exploring, in minute detail, the set of structural and dynamical changes taking place with FPP binding, peptide coordination and product formation. This study reveals the existence of a series of variational patterns involving the mechanistic events taking place at the active site of the enzyme, increasing in magnitude away from the active-site, demonstrating that relatively small-scale events such as substrate binding or product formation cause minor changes at the neighboring residues and corresponding helices, but ultimately induce much more dramatic effects on the more external regions of the enzyme.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
