Identification
- Generic Name
- Tipifarnib
- DrugBank Accession Number
- DB04960
- Background
Tipifarnib (R-115777) is a substance that is being studied in the treatment of acute myeloid leukemia (AML) and other types of cancer. It belongs to the family of drugs called farnesyltransferase inhibitors. It is also called Zarnestra. In June 2005, the FDA issued a Not Approvable Letter for Zarnestra.
- Type
- Small Molecule
- Groups
- Investigational
- Structure
Structure for Tipifarnib (DB04960)
- Weight
- Average: 489.396
Monoisotopic: 488.11706676 - Chemical Formula
- C27H22Cl2N4O
- Synonyms
- Tipifarnib
- Zarnestra
- External IDs
- R-115777
- R115777
Pharmacology
- Indication
Investigated for use/treatment in colorectal cancer, leukemia (myeloid), pancreatic cancer, and solid tumors.
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Prevent Adverse Drug Events TodayTap into our Clinical API for life-saving information on contraindications & blackbox warnings, population restrictions, harmful risks, & more.Avoid life-threatening adverse drug events with our Clinical API- Pharmacodynamics
R115777, a nonpeptidomimetic farnesyl transferase inhibitor, suppresses the growth of human pancreatic adenocarcinoma cell lines. This growth inhibition is associated with modulation in the phosphorylation levels of signal transducers and activators of transcription 3 (STAT3) and extracellular signal-regulated kinases (ERK).
- Mechanism of action
The farnesyltransferase inhibitors (FTIs) are a class of experimental cancer drugs that target protein farnesyltransferase with the downstream effect of preventing the proper functioning of the Ras protein, which is commonly abnormally active in cancer. After translation, RAS goes through four steps of modification: isoprenylation, proteolysis, methylation and palmitoylation. Isoprenylation involves the enzyme farnesyltransferase (FTase) transferring a farnesyl group from farnesyl pyrophosphate (FPP) to the pre-RAS protein. Also, a related enzyme geranylgeranyltransferase I (GGTase I) has the ability to transfer a geranylgeranyl group to K and N-RAS. Farnesyl is necessary to attach RAS to the cell membrane. Without attachment to the cell membrane, RAS is not able to transfer signals from membrane receptors (Reuter et al., 2000).
Target Actions Organism UProtein farnesyltransferase subunit beta Not Available Humans - Absorption
Not Available
- Volume of distribution
Not Available
- Protein binding
Not Available
- Metabolism
- Not Available
- Route of elimination
Not Available
- Half-life
Not Available
- Clearance
Not Available
- Adverse Effects
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Not Available
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs Browse all" title="About SNP Mediated Effects/ADRs" id="snp-actions-info" class="drug-info-popup" href="javascript:void(0);">
- Not Available
Interactions
- Drug Interactions Learn More" title="About Drug Interactions" id="structured-interactions-info" class="drug-info-popup" href="javascript:void(0);">
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Drug Interaction Integrate drug-drug
interactions in your softwareAmbroxol The risk or severity of methemoglobinemia can be increased when Tipifarnib is combined with Ambroxol. Articaine The risk or severity of methemoglobinemia can be increased when Tipifarnib is combined with Articaine. Benzocaine The risk or severity of methemoglobinemia can be increased when Tipifarnib is combined with Benzocaine. Benzyl alcohol The risk or severity of methemoglobinemia can be increased when Tipifarnib is combined with Benzyl alcohol. Bupivacaine The risk or severity of methemoglobinemia can be increased when Tipifarnib is combined with Bupivacaine. - Food Interactions
- Not Available
Products
Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.- International/Other Brands
- Zarnestra
Categories
- Drug Categories
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds known as linear diarylheptanoids. These are diarylheptanoids with an open heptane chain. The two aromatic rings are linked only by the heptane chain.
- Kingdom
- Organic compounds
- Super Class
- Phenylpropanoids and polyketides
- Class
- Diarylheptanoids
- Sub Class
- Linear diarylheptanoids
- Direct Parent
- Linear diarylheptanoids
- Alternative Parents
- Phenylquinolines / Phenylpyridines / Hydroquinolones / Hydroquinolines / Pyridinones / Aralkylamines / Chlorobenzenes / Aryl chlorides / N-substituted imidazoles / Heteroaromatic compounds show 8 more
- Substituents
- 4-phenylpyridine / Amine / Aralkylamine / Aromatic heteropolycyclic compound / Aryl chloride / Aryl halide / Azacycle / Azole / Benzenoid / Chlorobenzene show 25 more
- Molecular Framework
- Aromatic heteropolycyclic compounds
- External Descriptors
- Not Available
- Affected organisms
- Humans and other mammals
Chemical Identifiers
- UNII
- MAT637500A
- CAS number
- 192185-72-1
- InChI Key
- PLHJCIYEEKOWNM-HHHXNRCGSA-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
- IUPAC Name
- 6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-1,2-dihydroquinolin-2-one
- SMILES
- CN1C=NC=C1[C@@](N)(C1=CC=C(Cl)C=C1)C1=CC2=C(C=C1)N(C)C(=O)C=C2C1=CC(Cl)=CC=C1
References
- General References
- Martin LA, Head JE, Pancholi S, Salter J, Quinn E, Detre S, Kaye S, Howes A, Dowsett M, Johnston SR: The farnesyltransferase inhibitor R115777 (tipifarnib) in combination with tamoxifen acts synergistically to inhibit MCF-7 breast cancer cell proliferation and cell cycle progression in vitro and in vivo. Mol Cancer Ther. 2007 Sep;6(9):2458-67. [Article]
- Wang CC, Liao YP, Mischel PS, Iwamoto KS, Cacalano NA, McBride WH: HDJ-2 as a target for radiosensitization of glioblastoma multiforme cells by the farnesyltransferase inhibitor R115777 and the role of the p53/p21 pathway. Cancer Res. 2006 Jul 1;66(13):6756-62. [Article]
- External Links
- PubChem Compound
- 159324
- PubChem Substance
- 175426920
- ChemSpider
- 140122
- BindingDB
- 50370385
- ChEBI
- 141969
- ChEMBL
- CHEMBL289228
- ZINC
- ZINC000024809155
- PDBe Ligand
- JAN
- Wikipedia
- Tipifarnib
- PDB Entries
- 1sa4 / 1x81 / 3sfx / 4lng
Clinical Trials
- Clinical Trials Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
- Not Available
- Prices
- Not Available
- Patents
- Not Available
Properties
- State
- Solid
- Experimental Properties
- Not Available
- Predicted Properties
Property Value Source Water Solubility 0.000478 mg/mL ALOGPS logP 4.77 ALOGPS logP 4.69 Chemaxon logS -6 ALOGPS pKa (Strongest Basic) 7.5 Chemaxon Physiological Charge 1 Chemaxon Hydrogen Acceptor Count 3 Chemaxon Hydrogen Donor Count 1 Chemaxon Polar Surface Area 64.15 Å2 Chemaxon Rotatable Bond Count 4 Chemaxon Refractivity 148.2 m3·mol-1 Chemaxon Polarizability 50.16 Å3 Chemaxon Number of Rings 5 Chemaxon Bioavailability 1 Chemaxon Rule of Five Yes Chemaxon Ghose Filter No Chemaxon Veber's Rule No Chemaxon MDDR-like Rule No Chemaxon - Predicted ADMET Features
Property Value Probability Human Intestinal Absorption + 0.9963 Blood Brain Barrier + 0.9369 Caco-2 permeable + 0.6126 P-glycoprotein substrate Non-substrate 0.573 P-glycoprotein inhibitor I Non-inhibitor 0.8624 P-glycoprotein inhibitor II Non-inhibitor 0.742 Renal organic cation transporter Non-inhibitor 0.7321 CYP450 2C9 substrate Non-substrate 0.818 CYP450 2D6 substrate Non-substrate 0.8465 CYP450 3A4 substrate Substrate 0.6936 CYP450 1A2 substrate Inhibitor 0.8831 CYP450 2C9 inhibitor Non-inhibitor 0.5646 CYP450 2D6 inhibitor Non-inhibitor 0.8978 CYP450 2C19 inhibitor Non-inhibitor 0.7466 CYP450 3A4 inhibitor Inhibitor 0.7116 CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.6269 Ames test Non AMES toxic 0.598 Carcinogenicity Non-carcinogens 0.9073 Biodegradation Not ready biodegradable 1.0 Rat acute toxicity 2.6789 LD50, mol/kg Not applicable hERG inhibition (predictor I) Weak inhibitor 0.9942 hERG inhibition (predictor II) Inhibitor 0.5288
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Spectrum Spectrum Type Splash Key Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS splash10-00di-0000900000-eb6a79c41790a011b7b5 Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS splash10-000i-0000900000-489f6a9598a25af72875 Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS splash10-00di-0000900000-bd1bc0600a78e7757f73 Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS splash10-0019-5100900000-95d4944314a8381ee1b5 Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS splash10-0089-2025900000-cd7edd62a113bea7e964 Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS splash10-0uel-9650200000-f0ee40cb8716828a085e Predicted 1H NMR Spectrum 1D NMR Not Applicable Predicted 13C NMR Spectrum 1D NMR Not Applicable - Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 199.95505 predictedDeepCCS 1.0 (2019) [M+H]+ 202.35063 predictedDeepCCS 1.0 (2019) [M+Na]+ 208.26314 predictedDeepCCS 1.0 (2019)
Targets
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- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- General Function
- Zinc ion binding
- Specific Function
- Essential subunit of the farnesyltransferase complex. Catalyzes the transfer of a farnesyl moiety from farnesyl diphosphate to a cysteine at the fourth position from the C-terminus of several prote...
- Gene Name
- FNTB
- Uniprot ID
- P49356
- Uniprot Name
- Protein farnesyltransferase subunit beta
- Molecular Weight
- 48773.2 Da
References
- Venkatasubbarao K, Choudary A, Freeman JW: Farnesyl transferase inhibitor (R115777)-induced inhibition of STAT3(Tyr705) phosphorylation in human pancreatic cancer cell lines require extracellular signal-regulated kinases. Cancer Res. 2005 Apr 1;65(7):2861-71. [Article]
Transporters
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- General Function
- Xenobiotic-transporting atpase activity
- Specific Function
- Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
- Gene Name
- ABCB1
- Uniprot ID
- P08183
- Uniprot Name
- Multidrug resistance protein 1
- Molecular Weight
- 141477.255 Da
References
- Medeiros BC, Landau HJ, Morrow M, Lockerbie RO, Pitts T, Eckhardt SG: The farnesyl transferase inhibitor, tipifarnib, is a potent inhibitor of the MDR1 gene product, P-glycoprotein, and demonstrates significant cytotoxic synergism against human leukemia cell lines. Leukemia. 2007 Apr;21(4):739-46. Epub 2007 Feb 1. [Article]
- Karp JE, Lancet JE: Tipifarnib in the treatment of newly diagnosed acute myelogenous leukemia. Biologics. 2008 Sep;2(3):491-500. doi: 10.2147/btt.s3485. [Article]
Drug created at October 21, 2007 22:23 / Updated at January 14, 2023 19:02