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
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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Contraindications & Blackbox Warnings
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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).

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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Toxicity

Not Available

Pathways
Not Available
Pharmacogenomic Effects/ADRsBrowse all" title="" id="snp-actions-info" class="drug-info-popup" href="javascript:void(0);">
Not Available

Interactions

Drug InteractionsLearn More" title="" 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
Darbepoetin阿尔法 The risk or severity of Thrombosis can be increased when Darbepoetin alfa is combined with Tipifarnib.
Erythropoietin The risk or severity of Thrombosis can be increased when Erythropoietin is combined with Tipifarnib.
Methoxy polyethylene glycol-epoetin beta The risk or severity of Thrombosis can be increased when Methoxy polyethylene glycol-epoetin beta is combined with Tipifarnib.
Peginesatide The risk or severity of Thrombosis can be increased when Peginesatide is combined with Tipifarnib.
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Food Interactions
Not Available

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International/Other Brands
Zarnestra

Categories

Drug Categories
Chemical TaxonomyProvided byClassyfire
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

一般引用
  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. [Article]
  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. [Article]
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 TrialsLearn More" title="" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">
Phase Status Purpose Conditions Count
3 Completed Treatment Acute Myeloid Leukemia (AML) 1
3 Completed Treatment Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome/Adult Acute Megakaryoblastic Leukemia (M7)/Adult Acute Monocytic 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 Acute Myeloid Leukemia, Adult 1
3 Completed Treatment Neoplasms, Pancreatic 1
2 Active Not Recruiting Treatment Urothelial Carcinoma 1
2 Completed Prevention Neurofibromatosis Type I/Plexiform Neurofibromas (PN) 1
2 Completed Treatment Acute Myeloid Leukemia (AML) 1
2 Completed Treatment Acute Myeloid Leukemia With Multilineage Dysplasia Following Myelodysplastic Syndrome/Adult Acute Basophilic Leukemia/Adult Acute Eosinophilic Leukemia/成人急性红细胞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 Leukemia 1
2 Completed Treatment Acute 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 Leukemia 1
2 Completed Treatment Adenocarcinomas of the Pancreas/Stage II Pancreatic Cancer/Stage III Pancreatic Cancer 1
2 Completed Treatment 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 in Remission/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)/Recurrent Acute Myeloid Leukemia, Adult/Untreated Adult Acute Myeloid Leukemia 1

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规则 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
致癌性 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
ADMET data is predicted usingadmetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

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

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
分子量
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. [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
分子量
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. [Article]
  2. 卡普我,柳叶刀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 February 21, 2021 18:51