Linifanib

Identification

Name
Linifanib
Accession Number
DB06080
Description

Linifanib (ABT-869) is a small molecule vascular endothelial growth factor (VEGF) receptor-based kinase inhibitor that is designed to suppress tumor growth by preventing the formation of new blood vessels that supply the tumor with oxygen and nutrients and by inhibiting key angiogenic signaling pathways. Linifanib is intended for the treatment of hematologic malignancies and the solid tumors.

Type
Small Molecule
Groups
Investigational
Structure
Thumb
Weight
Average: 375.407
Monoisotopic: 375.149538383
Chemical Formula
C21H18FN5O
Synonyms
  • ABT-869
  • Linifanib
External IDs
  • A-741439
  • RG-3635

Pharmacology

Pharmacology
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Indication

Investigated for use/treatment in leukemia (myeloid), myelodysplastic syndrome, and solid tumors.

Contraindications & Blackbox Warnings
Contraindications
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Pharmacodynamics

ABT-869 was effective in a broad range of cancers including small cell lung carcinoma, colon carcinoma, breast carcinoma and MV4-11 tumors in vitro and in vivo. ABT-869 induced significant apoptosis in cells with FLT3 mutation in vitro (IC50 value of 4 nM) and profound anti-leukemic effect in a mouse xenograft model. However, in vitro ABT-869 only shows minimal cytotoxic effect on AML cells with wild-type FLT3. Based on the preclinical studies suggesting the role of VEGF pathways in leukemogenesis, it is likely that the anti-leukemic effect of ABT-869 will be best evaluated in vivo.

Mechanism of action

ABT-869, a multi-targeted receptor tyrosine kinase inhibitor, has been shown to inhibit of all members of the VEGF and PDGF receptor families (e.g., KDR IC50 value of 4 nM), and have less activity (IC50 values >1 µM) against unrelated receptor tyrosine kinases, soluble tyrosine kinases and serine/threonine kinases. In addition, it exhibits potent anti-proliferative and apoptotic effects on tumor cells dependent on mutant, constitutively active, FLT3 and KIT kinases.

TargetActionsOrganism
UReceptor-type tyrosine-protein kinase FLT3Not AvailableHumans
UVascular endothelial growth factor receptor 1Not AvailableHumans
UVascular endothelial growth factor receptor 2Not AvailableHumans
UVascular endothelial growth factor receptor 3Not AvailableHumans
UMast/stem cell growth factor receptor KitNot AvailableHumans
UMacrophage colony-stimulating factor 1 receptorNot 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
Medicalerrors
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Toxicity
Not Available
Affected organisms
Not Available
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.
Not Available
Food Interactions
Not Available

Categories

Drug Categories
Classification
Not classified

Chemical Identifiers

UNII
CO93X137CW
CAS number
796967-16-3
InChI Key
MPVGZUGXCQEXTM-UHFFFAOYSA-N
InChI
InChI=1S/C21H18FN5O/c1-12-5-10-16(22)18(11-12)25-21(28)24-14-8-6-13(7-9-14)15-3-2-4-17-19(15)20(23)27-26-17/h2-11H,1H3,(H3,23,26,27)(H2,24,25,28)
IUPAC Name
3-[4-(3-amino-1H-indazol-4-yl)phenyl]-1-(2-fluoro-5-methylphenyl)urea
SMILES
CC1=CC(NC(=O)NC2=CC=C(C=C2)C2=C3C(N)=NNC3=CC=C2)=C(F)C=C1

References

General References
  1. Zhou J, Khng J, Jasinghe VJ, Bi C, Neo CH, Pan M, Poon LF, Xie Z, Yu H, Yeoh AE, Lu Y, Glaser KB, Albert DH, Davidsen SK, Chen CS: In vivo activity of ABT-869, a multi-target kinase inhibitor, against acute myeloid leukemia with wild-type FLT3 receptor. Leuk Res. 2008 Jul;32(7):1091-100. Epub 2007 Dec 26. [PubMed:18160102]
  2. Guo J, Marcotte PA, McCall JO, Dai Y, Pease LJ, Michaelides MR, Davidsen SK, Glaser KB: Inhibition of phosphorylation of the colony-stimulating factor-1 receptor (c-Fms) tyrosine kinase in transfected cells by ABT-869 and other tyrosine kinase inhibitors. Mol Cancer Ther. 2006 Apr;5(4):1007-13. [PubMed:16648572]
  3. Albert DH, Tapang P, Magoc TJ, Pease LJ, Reuter DR, Wei RQ, Li J, Guo J, Bousquet PF, Ghoreishi-Haack NS, Wang B, Bukofzer GT, Wang YC, Stavropoulos JA, Hartandi K, Niquette AL, Soni N, Johnson EF, McCall JO, Bouska JJ, Luo Y, Donawho CK, Dai Y, Marcotte PA, Glaser KB, Michaelides MR, Davidsen SK: Preclinical activity of ABT-869, a multitargeted receptor tyrosine kinase inhibitor. Mol Cancer Ther. 2006 Apr;5(4):995-1006. [PubMed:16648571]
PubChem Substance
347910329
ChemSpider
9660475
BindingDB
21079
ChEBI
91435
ChEMBL
CHEMBL223360
ZINC
ZINC000006718813
Wikipedia
Linifanib

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3TerminatedTreatmentAdenocarcinomas / Carcinoma NOS / Digestive System Diseases / Digestive System Neoplasms / Hepatocellular Carcinoma / Hepatocellular Carcinoma Non-resectable / Liver Diseases / Neoplasms / Neoplasms by Histologic Type / Neoplasms by Site / Neoplasms, Glandular and Epithelial / Neoplasms, Hepatic / Recurrent Hepatocellular Carcinoma1
2CompletedTreatmentAdenocarcinoma of the Colon / Adenocarcinoma of the Rectum / Advanced Colorectal Cancer1
2CompletedTreatmentAdvanced Hepatocellular Carcinoma1
2CompletedTreatmentAdvanced or Metastatic Non-Small Cell Lung Cancer1
2CompletedTreatmentAdvanced Renal Cell Carcinoma1
2CompletedTreatmentMetastatic Breast Cancer1
2CompletedTreatmentNon-Small Cell Lung Carcinoma (NSCLC)1
2TerminatedTreatmentRecurrent Colon Cancer / Recurrent Rectal Cancer / Stage IVA Colon Cancer / Stage IVA Rectal Cancer / Stage IVB Colon Cancer / Stage IVB Rectal Cancer1
1CompletedBasic ScienceAdvanced Solid Tumors4
1CompletedBasic ScienceTumors, Solid1

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 Solubility0.00546 mg/mLALOGPS
logP4.2ALOGPS
logP4.51ChemAxon
logS-4.8ALOGPS
pKa (Strongest Acidic)10.4ChemAxon
pKa (Strongest Basic)3.37ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count4ChemAxon
Polar Surface Area95.83 Å2ChemAxon
Rotatable Bond Count3ChemAxon
Refractivity111.48 m3·mol-1ChemAxon
Polarizability38.98 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
Not Available

Targets

Drugtargets
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Kind
Protein
Organism
Humans
Pharmacological action
Unknown
General Function
Vascular endothelial growth factor-activated receptor activity
Specific Function
Tyrosine-protein kinase that acts as cell-surface receptor for the cytokine FLT3LG and regulates differentiation, proliferation and survival of hematopoietic progenitor cells and of dendritic cells...
Gene Name
FLT3
Uniprot ID
P36888
Uniprot Name
Receptor-type tyrosine-protein kinase FLT3
Molecular Weight
112902.51 Da
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
General Function
Vegf-b-activated receptor activity
Specific Function
Tyrosine-protein kinase that acts as a cell-surface receptor for VEGFA, VEGFB and PGF, and plays an essential role in the development of embryonic vasculature, the regulation of angiogenesis, cell ...
Gene Name
FLT1
Uniprot ID
P17948
Uniprot Name
Vascular endothelial growth factor receptor 1
Molecular Weight
150767.185 Da
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
General Function
Vascular endothelial growth factor-activated receptor activity
Specific Function
Tyrosine-protein kinase that acts as a cell-surface receptor for VEGFA, VEGFC and VEGFD. Plays an essential role in the regulation of angiogenesis, vascular development, vascular permeability, and ...
Gene Name
KDR
Uniprot ID
P35968
Uniprot Name
Vascular endothelial growth factor receptor 2
Molecular Weight
151525.555 Da
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
General Function
Vascular endothelial growth factor-activated receptor activity
Specific Function
Tyrosine-protein kinase that acts as a cell-surface receptor for VEGFC and VEGFD, and plays an essential role in adult lymphangiogenesis and in the development of the vascular network and the cardi...
Gene Name
FLT4
Uniprot ID
P35916
Uniprot Name
Vascular endothelial growth factor receptor 3
Molecular Weight
152755.94 Da
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
General Function
Transmembrane receptor protein tyrosine kinase activity
Specific Function
Tyrosine-protein kinase that acts as cell-surface receptor for the cytokine KITLG/SCF and plays an essential role in the regulation of cell survival and proliferation, hematopoiesis, stem cell main...
Gene Name
KIT
Uniprot ID
P10721
Uniprot Name
Mast/stem cell growth factor receptor Kit
Molecular Weight
109863.655 Da
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
General Function
Protein homodimerization activity
Specific Function
Tyrosine-protein kinase that acts as cell-surface receptor for CSF1 and IL34 and plays an essential role in the regulation of survival, proliferation and differentiation of hematopoietic precursor ...
Gene Name
CSF1R
Uniprot ID
P07333
Uniprot Name
Macrophage colony-stimulating factor 1 receptor
Molecular Weight
107982.955 Da

Drug created on November 18, 2007 18:29 / Updated on April 07, 2021 09:52