Farnesyltransferase inhibitors: a comprehensive review based on quantitative structural analysis.
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 pharmacokinetic properties in the clinical studies.
REQUIMTE, Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade do Porto, s/n, Rua do Campo Alegre, 4169-007 Porto, Portugal. pafernan@fc.up.pt.
N S H N
NS
Moorthy
S F
SF
Sousa
M J
MJ
Ramos
P A
PA
Fernandes
D000970:Antineoplastic Agents / Q000737:chemistry* / Q000627:therapeutic use; D001688:Biological Products / Q000737:chemistry / Q000378:metabolism; D002986:Clinical Trials as Topic; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000627:therapeutic use; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D010880:Piperidines / Q000737:chemistry / Q000627:therapeutic use; D011725:Pyridines / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D021281:Quantitative Structure-Activity Relationship; D015363:Quinolones / Q000737:chemistry / Q000627:therapeutic use; D003986:Dibenzocycloheptenes
D000970:Antineoplastic Agents; D001688:Biological Products; D004791:Enzyme Inhibitors; D051231:Farnesyltranstransferase; D010880:Piperidines; D011725:Pyridines; D015363:Quinolones; C530645:AZD3409; C115354:lonafarnib; D003986:Dibenzocycloheptenes; C402769:tipifarnib