Details
Stereochemistry | ACHIRAL |
Molecular Formula | C21H18FN5O |
Molecular Weight | 375.3989 |
Optical Activity | NONE |
Defined Stereocenters | 0 / 0 |
E/Z Centers | 0 |
Charge | 0 |
SHOW SMILES / InChI
SMILES
CC1=CC(NC(=O)NC2=CC=C(C=C2)C3=C4C(N)=NNC4=CC=C3)=C(F)C=C1
InChI
InChIKey=MPVGZUGXCQEXTM-UHFFFAOYSA-N
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)
Linifanib (ABT-869) is a structurally novel, receptor tyrosine kinase (RTK) inhibitor that is a potent inhibitor of members of the vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) receptor families, but has much less activity against unrelated RTKs, soluble tyrosine kinases, or serine/threonine kinases. Linifanib (ABT-869) does not have a general antiproliferative effect due to its high dose requirement. However, it may exhibit potent antiproliferative and apoptotic effects on tumor cells whose proliferation is dependent on mutant kinases, such as FMS-related tyrosine kinase receptor-3 (FLT3). Linifanib (ABT-869) was in phase III clinical trial for the treatment of hepatocellular carcinoma, but the study failed to meet the primary end point.
Originator
Approval Year
Targets
Primary Target | Pharmacology | Condition | Potency |
---|---|---|---|
Target ID: CHEMBL2095227 |
4.0 nM [IC50] | ||
Target ID: CHEMBL1844 |
3.0 nM [IC50] | ||
Target ID: CHEMBL1913 |
66.0 nM [IC50] | ||
Target ID: CHEMBL1974 |
4.0 nM [IC50] | ||
Target ID: CHEMBL1868 |
3.0 nM [IC50] | ||
Target ID: CHEMBL1936 |
14.0 nM [IC50] |
Conditions
Condition | Modality | Targets | Highest Phase | Product |
---|---|---|---|---|
Primary | LINIFANIB Approved UseUnknown |
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Primary | LINIFANIB Approved UseUnknown |
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Primary | LINIFANIB Approved UseUnknown |
Doses
Dose | Population | Adverse events |
---|---|---|
0.3 mg/kg 1 times / day multiple, oral MTD Dose: 0.3 mg/kg, 1 times / day Route: oral Route: multiple Dose: 0.3 mg/kg, 1 times / day Sources: Page: p.4721 |
unhealthy, ADULT n = 3 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 3 Sources: Page: p.4721 |
DLT: Proteinuria, Hypertension... Dose limiting toxicities: Proteinuria (grade 3, 33.3%) Sources: Page: p.4721Hypertension (grade 3, 66.7%) |
0.25 mg/kg 1 times / day multiple, oral RP2D Dose: 0.25 mg/kg, 1 times / day Route: oral Route: multiple Dose: 0.25 mg/kg, 1 times / day Sources: Page: p.1424 |
unhealthy, ADULT n = 74 Health Status: unhealthy Condition: Non-small cell lung cancer Age Group: ADULT Sex: M+F Food Status: FASTED Population Size: 74 Sources: Page: p.1424 |
Disc. AE: Proteinuria, Palmar-plantar erythrodysesthesia syndrome... AEs leading to discontinuation/dose reduction: Proteinuria (10.8%) Sources: Page: p.1424Palmar-plantar erythrodysesthesia syndrome (9.5%) Hypertension (10.8%) |
0.25 mg/kg 1 times / day multiple, oral RP2D Dose: 0.25 mg/kg, 1 times / day Route: oral Route: multiple Dose: 0.25 mg/kg, 1 times / day Sources: Page: p.1479 |
unhealthy, ADULT n = 6 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: FASTED Population Size: 6 Sources: Page: p.1479 |
DLT: T wave inversion... Dose limiting toxicities: T wave inversion (grade 1, 16.7%) Sources: Page: p.1479 |
0.25 mg/kg 1 times / day multiple, oral RP2D Dose: 0.25 mg/kg, 1 times / day Route: oral Route: multiple Dose: 0.25 mg/kg, 1 times / day Sources: Page: p.384 |
unhealthy, ADULT n = 44 Health Status: unhealthy Condition: hepatocellular carcinoma Age Group: ADULT Sex: M+F Food Status: FASTED Population Size: 44 Sources: Page: p.384 |
Disc. AE: Thrombocytopenia, Intracranial hemorrhag... AEs leading to discontinuation/dose reduction: Thrombocytopenia (2.3%) Sources: Page: p.384Intracranial hemorrhag (grade 5, 2.3%) Liver failure (grade 5, 2.3%) Hypertension (2.3%) Palmar-plantar erythrodysaesthesia syndrome (13.6%) Proteinuria (6.8%) Palmar-plantar erythrodysesthesia syndrome (15.9%) Skin rash (6.8%) Fatigue (6.8%) Hypertension (20.5%) Hypertension (20.5%) Proteinuria (13.6%) |
0.25 mg/kg 1 times / day multiple, oral RP2D Dose: 0.25 mg/kg, 1 times / day Route: oral Route: multiple Dose: 0.25 mg/kg, 1 times / day Sources: Page: p.4721 |
unhealthy, ADULT n = 12 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 12 Sources: Page: p.4721 |
DLT: Proteinuria, Hypertension... Dose limiting toxicities: Proteinuria (grade 3, 16.7%) Sources: Page: p.4721Hypertension (grade 2, 16.7%) |
AEs
AE | Significance | Dose | Population |
---|---|---|---|
Proteinuria | grade 3, 33.3% DLT |
0.3 mg/kg 1 times / day multiple, oral MTD Dose: 0.3 mg/kg, 1 times / day Route: oral Route: multiple Dose: 0.3 mg/kg, 1 times / day Sources: Page: p.4721 |
unhealthy, ADULT n = 3 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 3 Sources: Page: p.4721 |
Hypertension | grade 3, 66.7% DLT |
0.3 mg/kg 1 times / day multiple, oral MTD Dose: 0.3 mg/kg, 1 times / day Route: oral Route: multiple Dose: 0.3 mg/kg, 1 times / day Sources: Page: p.4721 |
unhealthy, ADULT n = 3 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 3 Sources: Page: p.4721 |
Hypertension | 10.8% Disc. AE |
0.25 mg/kg 1 times / day multiple, oral RP2D Dose: 0.25 mg/kg, 1 times / day Route: oral Route: multiple Dose: 0.25 mg/kg, 1 times / day Sources: Page: p.1424 |
unhealthy, ADULT n = 74 Health Status: unhealthy Condition: Non-small cell lung cancer Age Group: ADULT Sex: M+F Food Status: FASTED Population Size: 74 Sources: Page: p.1424 |
Proteinuria | 10.8% Disc. AE |
0.25 mg/kg 1 times / day multiple, oral RP2D Dose: 0.25 mg/kg, 1 times / day Route: oral Route: multiple Dose: 0.25 mg/kg, 1 times / day Sources: Page: p.1424 |
unhealthy, ADULT n = 74 Health Status: unhealthy Condition: Non-small cell lung cancer Age Group: ADULT Sex: M+F Food Status: FASTED Population Size: 74 Sources: Page: p.1424 |
Palmar-plantar erythrodysesthesia syndrome | 9.5% Disc. AE |
0.25 mg/kg 1 times / day multiple, oral RP2D Dose: 0.25 mg/kg, 1 times / day Route: oral Route: multiple Dose: 0.25 mg/kg, 1 times / day Sources: Page: p.1424 |
unhealthy, ADULT n = 74 Health Status: unhealthy Condition: Non-small cell lung cancer Age Group: ADULT Sex: M+F Food Status: FASTED Population Size: 74 Sources: Page: p.1424 |
T wave inversion | grade 1, 16.7% DLT, Disc. AE |
0.25 mg/kg 1 times / day multiple, oral RP2D Dose: 0.25 mg/kg, 1 times / day Route: oral Route: multiple Dose: 0.25 mg/kg, 1 times / day Sources: Page: p.1479 |
unhealthy, ADULT n = 6 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: FASTED Population Size: 6 Sources: Page: p.1479 |
Palmar-plantar erythrodysaesthesia syndrome | 13.6% Disc. AE |
0.25 mg/kg 1 times / day multiple, oral RP2D Dose: 0.25 mg/kg, 1 times / day Route: oral Route: multiple Dose: 0.25 mg/kg, 1 times / day Sources: Page: p.384 |
unhealthy, ADULT n = 44 Health Status: unhealthy Condition: hepatocellular carcinoma Age Group: ADULT Sex: M+F Food Status: FASTED Population Size: 44 Sources: Page: p.384 |
Proteinuria | 13.6% Disc. AE |
0.25 mg/kg 1 times / day multiple, oral RP2D Dose: 0.25 mg/kg, 1 times / day Route: oral Route: multiple Dose: 0.25 mg/kg, 1 times / day Sources: Page: p.384 |
unhealthy, ADULT n = 44 Health Status: unhealthy Condition: hepatocellular carcinoma Age Group: ADULT Sex: M+F Food Status: FASTED Population Size: 44 Sources: Page: p.384 |
Palmar-plantar erythrodysesthesia syndrome | 15.9% Disc. AE |
0.25 mg/kg 1 times / day multiple, oral RP2D Dose: 0.25 mg/kg, 1 times / day Route: oral Route: multiple Dose: 0.25 mg/kg, 1 times / day Sources: Page: p.384 |
unhealthy, ADULT n = 44 Health Status: unhealthy Condition: hepatocellular carcinoma Age Group: ADULT Sex: M+F Food Status: FASTED Population Size: 44 Sources: Page: p.384 |
Hypertension | 2.3% Disc. AE |
0.25 mg/kg 1 times / day multiple, oral RP2D Dose: 0.25 mg/kg, 1 times / day Route: oral Route: multiple Dose: 0.25 mg/kg, 1 times / day Sources: Page: p.384 |
unhealthy, ADULT n = 44 Health Status: unhealthy Condition: hepatocellular carcinoma Age Group: ADULT Sex: M+F Food Status: FASTED Population Size: 44 Sources: Page: p.384 |
Thrombocytopenia | 2.3% Disc. AE |
0.25 mg/kg 1 times / day multiple, oral RP2D Dose: 0.25 mg/kg, 1 times / day Route: oral Route: multiple Dose: 0.25 mg/kg, 1 times / day Sources: Page: p.384 |
unhealthy, ADULT n = 44 Health Status: unhealthy Condition: hepatocellular carcinoma Age Group: ADULT Sex: M+F Food Status: FASTED Population Size: 44 Sources: Page: p.384 |
Hypertension | 20.5% Disc. AE |
0.25 mg/kg 1 times / day multiple, oral RP2D Dose: 0.25 mg/kg, 1 times / day Route: oral Route: multiple Dose: 0.25 mg/kg, 1 times / day Sources: Page: p.384 |
unhealthy, ADULT n = 44 Health Status: unhealthy Condition: hepatocellular carcinoma Age Group: ADULT Sex: M+F Food Status: FASTED Population Size: 44 Sources: Page: p.384 |
Hypertension | 20.5% Disc. AE |
0.25 mg/kg 1 times / day multiple, oral RP2D Dose: 0.25 mg/kg, 1 times / day Route: oral Route: multiple Dose: 0.25 mg/kg, 1 times / day Sources: Page: p.384 |
unhealthy, ADULT n = 44 Health Status: unhealthy Condition: hepatocellular carcinoma Age Group: ADULT Sex: M+F Food Status: FASTED Population Size: 44 Sources: Page: p.384 |
Fatigue | 6.8% Disc. AE |
0.25 mg/kg 1 times / day multiple, oral RP2D Dose: 0.25 mg/kg, 1 times / day Route: oral Route: multiple Dose: 0.25 mg/kg, 1 times / day Sources: Page: p.384 |
unhealthy, ADULT n = 44 Health Status: unhealthy Condition: hepatocellular carcinoma Age Group: ADULT Sex: M+F Food Status: FASTED Population Size: 44 Sources: Page: p.384 |
Proteinuria | 6.8% Disc. AE |
0.25 mg/kg 1 times / day multiple, oral RP2D Dose: 0.25 mg/kg, 1 times / day Route: oral Route: multiple Dose: 0.25 mg/kg, 1 times / day Sources: Page: p.384 |
unhealthy, ADULT n = 44 Health Status: unhealthy Condition: hepatocellular carcinoma Age Group: ADULT Sex: M+F Food Status: FASTED Population Size: 44 Sources: Page: p.384 |
Skin rash | 6.8% Disc. AE |
0.25 mg/kg 1 times / day multiple, oral RP2D Dose: 0.25 mg/kg, 1 times / day Route: oral Route: multiple Dose: 0.25 mg/kg, 1 times / day Sources: Page: p.384 |
unhealthy, ADULT n = 44 Health Status: unhealthy Condition: hepatocellular carcinoma Age Group: ADULT Sex: M+F Food Status: FASTED Population Size: 44 Sources: Page: p.384 |
Intracranial hemorrhag | grade 5, 2.3% Disc. AE |
0.25 mg/kg 1 times / day multiple, oral RP2D Dose: 0.25 mg/kg, 1 times / day Route: oral Route: multiple Dose: 0.25 mg/kg, 1 times / day Sources: Page: p.384 |
unhealthy, ADULT n = 44 Health Status: unhealthy Condition: hepatocellular carcinoma Age Group: ADULT Sex: M+F Food Status: FASTED Population Size: 44 Sources: Page: p.384 |
Liver failure | grade 5, 2.3% Disc. AE |
0.25 mg/kg 1 times / day multiple, oral RP2D Dose: 0.25 mg/kg, 1 times / day Route: oral Route: multiple Dose: 0.25 mg/kg, 1 times / day Sources: Page: p.384 |
unhealthy, ADULT n = 44 Health Status: unhealthy Condition: hepatocellular carcinoma Age Group: ADULT Sex: M+F Food Status: FASTED Population Size: 44 Sources: Page: p.384 |
Hypertension | grade 2, 16.7% DLT |
0.25 mg/kg 1 times / day multiple, oral RP2D Dose: 0.25 mg/kg, 1 times / day Route: oral Route: multiple Dose: 0.25 mg/kg, 1 times / day Sources: Page: p.4721 |
unhealthy, ADULT n = 12 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 12 Sources: Page: p.4721 |
Proteinuria | grade 3, 16.7% DLT |
0.25 mg/kg 1 times / day multiple, oral RP2D Dose: 0.25 mg/kg, 1 times / day Route: oral Route: multiple Dose: 0.25 mg/kg, 1 times / day Sources: Page: p.4721 |
unhealthy, ADULT n = 12 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 12 Sources: Page: p.4721 |
Overview
CYP3A4 | CYP2C9 | CYP2D6 | hERG |
---|---|---|---|
OverviewOther
Other Inhibitor | Other Substrate | Other Inducer |
---|---|---|
Drug as perpetrator
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
no [Inhibition 50 uM] | ||||
unlikely [Inhibition 50 uM] | ||||
weak [Inhibition 50 uM] | ||||
yes [Inhibition 1 uM] |
Drug as victim
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
yes |
Tox targets
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
PubMed
Title | Date | PubMed |
---|---|---|
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. | 2006 Apr |
|
ABT-869, a promising multi-targeted tyrosine kinase inhibitor: from bench to bedside. | 2009 Jul 30 |
|
Effect of the multitargeted receptor tyrosine kinase inhibitor, ABT-869 [N-(4-(3-amino-1H-indazol-4-yl)phenyl)-N'-(2-fluoro-5-methylphenyl)urea], on blood pressure in conscious rats and mice: reversal with antihypertensive agents and effect on tumor growth inhibition. | 2009 Jun |
|
Activation state-dependent binding of small molecule kinase inhibitors: structural insights from biochemistry. | 2010 Nov 24 |
|
Comprehensive analysis of kinase inhibitor selectivity. | 2011 Oct 30 |
|
A selective chemical probe for exploring the role of CDK8 and CDK19 in human disease. | 2015 Dec |
Sample Use Guides
In Vivo Use Guide
Sources: https://www.ncbi.nlm.nih.gov/pubmed/25488963
Linifanib 17.5 mg once daily.
Route of Administration:
Oral
In Vitro Use Guide
Sources: https://www.ncbi.nlm.nih.gov/pubmed/16648571
Linifanib (ABT-869) is a receptor tyrosine kinase (RTK) inhibitor that is a potent inhibitor of members of the vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) receptor families (e.g., KDR IC50 = 4 nmol/L) but has much less activity (IC50s > 1 uM/L) against unrelated RTKs, soluble tyrosine kinases, or serine/threonine kinases. The inhibition profile of ABT-869 is evident in cellular assays of RTK phosphorylation (IC50 = 2, 4, and 7 nmol/L for PDGFR-beta, KDR, and CSF-1R, respectively) and VEGF-stimulated proliferation (IC50 = 0.2 nmol/L for human endothelial cells).
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Classification Tree | Code System | Code | ||
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NCI_THESAURUS |
C1967
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NCI_THESAURUS |
C93259
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FDA ORPHAN DRUG |
240807
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FDA ORPHAN DRUG |
248007
Created by
admin on Sat Dec 16 16:31:41 GMT 2023 , Edited by admin on Sat Dec 16 16:31:41 GMT 2023
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Code System | Code | Type | Description | ||
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LINIFANIB
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UU-147
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11485656
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CO93X137CW
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9195
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100000126073
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SUB33027
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C71759
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DTXSID40229834
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796967-16-3
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DB06080
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CHEMBL223360
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ACTIVE MOIETY
METABOLITE ACTIVE (PARENT)