Farnesyltransferase Inhibitors: A Comprehensive Review Based on Quantitative Structural Analysis

Abstract

Farnesyltransferase inhibitors (FTIs) have mainly been used in cancer therapy. However, more recently, investigations on these inhibitors revealed that FTIs can be used for the treatment of other diseases such as Progeria, P. falciparum resistant malaria, Trypnosomatid, etc. Hence the development of novel FTIs is an important task for the drug discovery program. Initially, numerous peptidomimetic FTIs were developed from the template of CAAX (CVIM was the first pharmacophore model used as a peptidomimetic). Later, many non-peptidomimetic FTIs have been discovered with the structural modification of the peptidomimetics. The structural analysis of those developed FTIs by various researchers suggested that the presence of a heterocycle or a polar group in place of the thiol group is required for interaction with the Zn(2+) ion. The bulky naphthyl, quinolinyl, phenyl, phenothazine, etc in this position provide better hydrophobicity to the molecules which interact with the aromatic amino acid moieties in the hydrophobic pocket. A hydrophilic region with polar groups is necessary for the polar or hydrogen bonding interactions with the amino acids or water molecules in the active site. Many FTIs have been isolated from natural products, which possessed inhibitory activity against farnesyltransferase (FTase). Among them, pepticinnamin E (9R), fusidienol (9T), gliotoxin (9V), cylindrol A (9X), etc possessed potential FTase inhibitory activities and their structural features are comparable to those of the synthetic molecules. The clinical studies progressing on FTIs showed that tipifarnib in combination with bortezomib is used for the treatment of patients with advanced acute leukemias. Successful phase I and II studies are undergoing for tipifarnib alone or in combination with other drugs/radiation for the treatment of multiple myeloma, AML, breast cancer, mantle cell lymphoma, solid tumors, non-small cell lung cancer (NSCLC), pancreatic cancer, glioblastoma, etc. Phase I pharmacokinetic (maximum tolerated dose, toxicity) and pharmacodynamic studies of AZD3409 (an orally active double prodrug) is progressing on patients with solid malignancies taking 500 mg once a day. A phase II study is undergoing on lonafarnib alone and in combination with zoledronic acid and pravastatin for the treatment of Hutchinson-Gilford Progeria syndrome (HGPS) and progeroid laminopathies. Lonafarnib therapy improved cardiovascular status of children with HGPS, by improved peripheral arterial stiffness, bone structure and audiological status in the patients. Other important FTIs such as BMS-214662, LB42908, LB42708, etc are under clinical studies for the treatment of various cancers. This review concluded that the quantitative structural analysis report with an elaborative study on the natural product compounds provides ideas for development of novel molecules for the FTase inhibitory activity. The fragment based analysis is also needed to select the substituents, which provides significant inhibitory activities and can also have good pharmacoki...

Phenothiazine-based CaaX competitive inhibitors of human farnesyltransferase bearing a cysteine, methionine, serine or valine moiety as a new family of antitumoral compounds

“…[1][2][3][4][5][6] FTase is a heterodimeric zinc metalloenzyme, responsible for posttranslational modification and activation of Ras proteins. Ras proteins undergo three sequential enzymatic posttranslational modifications.…”

Molecular dynamic simulations and structure-based pharmacophore development for farnesyltransferase inhibitors discovery

“…Hence, medicinal chemists are working on different biological targets to develop novel molecules as anticancer agents 3 . Farnesyltransferase (FTase) is one of three prenyltransferase enzymes (farnesyltransferase (FTase), geranylgeranyltransferase-I (GGTase-I) and geranylgeranyltransferase-II (GGTase-II)) used by normal and malignant cells to catalyze covalent attachment of prenyl groups to 4300 polypeptides in the human proteome [4][5][6] . FTase has become a major target in the development of potential anticancer drugs and has also been used as an effective target for the development of drugs against Progeria and parasites diseases, such as P. falciparum-resistant malaria, trypanosomatid infections (African sleeping sickness), Chagas disease, Toxoplasmosis and Leishmaniasis and as antiviral agents [7][8][9][10][11][12][13][14] .…”

“…FTase modifies the oncogene Ras through the farnesyl pyrophosphate (FPP) intermediate by the farnesylation of a carboxyl terminus protein in the CAAX (tetrapeptide motif) (''C'' refers to the cysteine, ''A'' to any aliphatic amino acid often methionine, and ''X'' to any amino acid, glutamine or serine in FTase and leucine or phenylalanine in GGTase-1). The G-protein, Ras plays an important role in mediating cellular responses to growth signals and the appearance of its oncogenic mutants is associated to a high percentage of human cancers 6,15 . It could be related to the development of cancer by mutations in these proteins.…”

“…It could be related to the development of cancer by mutations in these proteins. The inhibition of FTase enzyme activity can be a better target for anticancer drug development and some FTase inhibitors, such as tipifarnib, lonafarnib, BMS214 662, L7, 78123 and SCH4, 4342 are currently being assessed in clinical trials for the treatment of human cancers 6,16,17 . Scientists have been working on the drug discovery field, using different approaches for drug discovery.…”

“…Computational methods are one of the prominent methods used nowadays to reduce the cost and time in the drug development program. Our research group has been working on this target for the last 10 years for the development of FTase inhibitors using computational-based approaches 3,6,18 .…”