Title:Farnesyltransferase Inhibitors: A Comprehensive Review Based on Quantitative Structural Analysis
Volume: 20
Issue: 38
Author(s): N. S.H.N. Moorthy, S. F. Sousa, M. J. Ramos and P. A. Fernandes
Affiliation:
Keywords:
Anticancer, farnesyltransferase inhibitors, natural products, QSAR, tipifarnib, lonafarnib.
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
Zn2+ 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 pharmacokinetic properties in the
clinical studies.
