Identification

Name
Tipifarnib
Accession Number
DB04960
Description

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
Thumb
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.

Contraindications & Blackbox Warnings
Learn about our commercial Contraindications & Blackbox Warnings data.
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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).

TargetActionsOrganism
UProtein farnesyltransferase subunit betaNot AvailableHumans
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
Learn about our commercial Adverse Effects data.
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Toxicity
Not Available
Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
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.
DrugInteraction
Darbepoetin alfaThe risk or severity of Thrombosis can be increased when Darbepoetin alfa is combined with Tipifarnib.
ErythropoietinThe risk or severity of Thrombosis can be increased when Erythropoietin is combined with Tipifarnib.
Methoxy polyethylene glycol-epoetin betaThe risk or severity of Thrombosis can be increased when Methoxy polyethylene glycol-epoetin beta is combined with Tipifarnib.
PeginesatideThe risk or severity of Thrombosis can be increased when Peginesatide is combined with Tipifarnib.
Additional Data Available
  • Extended Description
    Extended Description

    Extended description of the mechanism of action and particular properties of each drug interaction.

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  • Severity
    Severity

    A severity rating for each drug interaction, from minor to major.

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  • Evidence Level
    Evidence Level

    A rating for the strength of the evidence supporting each drug interaction.

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  • Action
    Action

    An effect category for each drug interaction. Know how this interaction affects the subject drug.

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Food Interactions
Not Available

Products

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

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-[(R)-amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-1,2-dihydroquinolin-2-one
SMILES
CN1C=NC=C1[[email protected]@](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
  1. 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. [PubMed:17876043]
  2. 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. [PubMed:16818651]
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
PhaseStatusPurposeConditionsCount
3CompletedTreatmentAcute Myeloid Leukemia (AML)1
3CompletedTreatmentAcute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome / Adult Acute Megakaryoblastic Leukemia / Adult Acute Monocytic Leukemia / Adult Acute Myeloid Leukemia / Adult Acute Myeloid Leukemia in Remission / Adult Acute Myeloid Leukemia With Inv(16)(p13.1q22); CBFB-MYH11 / Adult Acute Myeloid Leukemia With Maturation / Adult Acute Myeloid Leukemia With Minimal Differentiation / Adult Acute Myeloid Leukemia With t(16;16)(p13.1;q22); CBFB-MYH11 / Adult Acute Myeloid Leukemia With t(8;21); (q22; q22.1); RUNX1-RUNX1T1 / Adult Acute Myeloid Leukemia With t(9;11)(p22.3;q23.3); MLLT3-KMT2A / Adult Acute Myeloid Leukemia Without Maturation / Adult Acute Myelomonocytic Leukemia / Adult Erythroleukemia / Adult Pure Erythroid Leukemia / Alkylating Agent-Related Acute Myeloid Leukemia / Myelodysplastic Syndrome With Excess Blasts / Recurrent Adult Acute Myeloid Leukemia1
3CompletedTreatmentNeoplasms, Pancreatic1
2Active Not RecruitingTreatmentHRAS Mutant Tumor / Other Squamous Cell Carcinoma (SCC) With HRAS Mutant Tumor / Squamous Cell Carcinoma Head and Neck Cancer (HNSCC) / Thyroid Cancers1
2Active Not RecruitingTreatmentLeukemia, Myelomonocytic, Chronic1
2Active Not RecruitingTreatmentRelapsed or Refractory Peripheral T-cell Lymphoma1
2CompletedPreventionNeurofibromatosis Type I / Plexiform Neurofibroma1
2CompletedTreatmentAcute Myeloid Leukemia (AML)1
2CompletedTreatmentAcute Myeloid Leukemia With Multilineage Dysplasia Following Myelodysplastic Syndrome / Adult Acute Basophilic Leukemia / Adult Acute Eosinophilic Leukemia / Adult Acute Erythroid Leukemia (M6) / Adult Acute Megakaryoblastic Leukemia (M7) / Adult Acute Minimally Differentiated Myeloid Leukemia (M0) / Adult Acute Monoblastic Leukemia (M5a) / Adult Acute Monoblastic Leukemia and Acute Monocytic Leukemia (M5) / Adult Acute Monocytic Leukemia (M5b) / Adult Acute Myeloblastic Leukemia With Maturation (M2) / Adult Acute Myeloblastic Leukemia Without Maturation (M1) / Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities / Adult Acute Myeloid Leukemia With Del(5q) / Adult Acute Myeloid Leukemia With Inv(16)(p13;q22) / Adult Acute Myeloid Leukemia With T(16;16)(p13;q22) / Adult Acute Myeloid Leukemia With T(8;21)(q22;q22) / Adult Acute Myelomonocytic Leukemia (M4) / Adult Erythroleukemia (M6a) / Adult Pure Erythroid Leukemia (M6b) / Cellular Diagnosis, Adult Acute Myeloid Leukemia / Untreated Adult Acute Myeloid Leukemia1
2CompletedTreatmentAcute Myeloid Leukemia With Multilineage Dysplasia Following Myelodysplastic Syndrome / Adult Acute Megakaryoblastic Leukemia (M7) / Adult Acute Minimally Differentiated Myeloid Leukemia (M0) / Adult Acute Monoblastic Leukemia (M5a) / Adult Acute Monocytic Leukemia (M5b) / Adult Acute Myeloblastic Leukemia With Maturation (M2) / Adult Acute Myeloblastic Leukemia Without Maturation (M1) / Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities / Adult Acute Myeloid Leukemia With Del(5q) / Adult Acute Myeloid Leukemia With Inv(16)(p13;q22) / Adult Acute Myeloid Leukemia With T(16;16)(p13;q22) / Adult Acute Myeloid Leukemia With T(8;21)(q22;q22) / Adult Acute Myelomonocytic Leukemia (M4) / Adult Erythroleukemia (M6a) / Adult Pure Erythroid Leukemia (M6b) / Secondary Acute Myeloid Leukemia (Secondary AML, sAML) / Untreated Adult Acute Myeloid Leukemia1

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
PropertyValueSource
Water Solubility0.000478 mg/mLALOGPS
logP4.77ALOGPS
logP4.69ChemAxon
logS-6ALOGPS
pKa (Strongest Basic)7.74ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area64.15 Å2ChemAxon
Rotatable Bond Count4ChemAxon
Refractivity148.2 m3·mol-1ChemAxon
Polarizability50.16 Å3ChemAxon
Number of Rings5ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption+0.9963
Blood Brain Barrier+0.9369
Caco-2 permeable+0.6126
P-glycoprotein substrateNon-substrate0.573
P-glycoprotein inhibitor INon-inhibitor0.8624
P-glycoprotein inhibitor IINon-inhibitor0.742
Renal organic cation transporterNon-inhibitor0.7321
CYP450 2C9 substrateNon-substrate0.818
CYP450 2D6 substrateNon-substrate0.8465
CYP450 3A4 substrateSubstrate0.6936
CYP450 1A2 substrateInhibitor0.8831
CYP450 2C9 inhibitorNon-inhibitor0.5646
CYP450 2D6 inhibitorNon-inhibitor0.8978
CYP450 2C19 inhibitorNon-inhibitor0.7466
CYP450 3A4 inhibitorInhibitor0.7116
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.6269
Ames testNon AMES toxic0.598
CarcinogenicityNon-carcinogens0.9073
BiodegradationNot ready biodegradable1.0
Rat acute toxicity2.6789 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9942
hERG inhibition (predictor II)Inhibitor0.5288
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Targets

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
  1. 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. [PubMed:15805288]

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
  1. 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. [PubMed:17268526]
  2. 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. [PubMed:19707379]

Drug created on October 21, 2007 16:23 / Updated on June 12, 2020 10:52

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