Farnesyltransferase inhibitors: a comprehensive review based on quantitative structural analysis.

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