tipifarnib   Click here for help

GtoPdb Ligand ID: 8025

Synonyms: R-115777 | R115777
PDB Ligand
Compound class: Synthetic organic
Comment: Tipifarnib is a non-peptidomimetic competitive farnesyltransferase inhibitor (FTI) [4].
Click here for help
2D Structure
Click here for help
Click here for structure editor
Physico-chemical Properties
Click here for help
Hydrogen bond acceptors 3
Hydrogen bond donors 1
Rotatable bonds 4
Topological polar surface area 65.84
Molecular weight 488.12
XLogP 6.97
No. Lipinski's rules broken 1
Click here for help
Canonical SMILES Clc1ccc(cc1)C(c1cncn1C)(c1ccc2c(c1)c(cc(=O)n2C)c1cccc(c1)Cl)N
Isomeric SMILES Clc1ccc(cc1)[C@](c1cncn1C)(c1ccc2c(c1)c(cc(=O)n2C)c1cccc(c1)Cl)N
InChI InChI=1S/C27H22Cl2N4O/c1-32-16-31-15-25(32)27(30,18-6-9-20(28)10-7-18)19-8-11-24-23(13-19)22(14-26(34)33(24)2)17-4-3-5-21(29)12-17/h3-16H,30H2,1-2H3/t27-/m1/s1
No information available.
Summary of Clinical Use Click here for help
Tipifarnib has been assessed in Phase 2I clinical trials for acute myeloid leukemia (AML) and advanced pancreatic cancer. Phase 2 trials for breast cancer, glioblastoma, malignant melanoma and non-small cell lung cancer are ongoing. Click here to link to ClinicalTrials.gov's listing of all tipifarnib trials.
Mechanism Of Action and Pharmacodynamic Effects Click here for help
Tipifarnib inhibits the prenylation and therefore the membrane tethering capacity of RAS proteins, which are often hyper-activated in cancer. Loss of membrane anchorage leaves the RAS protein free in the cytosol where it is degraded. By reducing activity of RAS oncogenes tipifarnib inhibits cell growth, induces apoptosis, and inhibits angiogenesis [3]. However, the promise of FTIs has not been bourne out in clinical trials [2], perhaps due to redundancy in the system which sees geranylgeranyltransferase taking over the prenylation process, when farnesyltransferase is inhibited.