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BioAssay: AID 271973

Inhibition of FGFR1

2-aminothiazole (1) was discovered as a novel Src family kinase inhibitor template through screening of our internal compound collection. Optimization through successive structure-activity relationship iterations identified analogs 2 (Dasatinib, BMS-354825) and 12m as pan-Src inhibitors with nanomolar to subnanomolar potencies in biochemical and cellular assays. Molecular modeling was used to more ..
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 Tested Compounds
 Tested Compounds
All(2)
 
 
Unspecified(2)
 
 
 Tested Substances
 Tested Substances
All(2)
 
 
Unspecified(2)
 
 
 Related BioAssays
 Related BioAssays
AID: 271973
Data Source: ChEMBL (409132)
Depositor Category: Literature, Extracted
BioAssay Version:
Deposit Date: 2010-05-25
Modify Date: 2013-11-18

Data Table ( Complete ):           All
Target
Sequence: RecName: Full=Fibroblast growth factor receptor 1; Short=FGFR-1; AltName: Full=Basic fibroblast growth factor receptor 1; Short=BFGFR; Short=bFGF-R-1; AltName: Full=Fms-like tyrosine kinase 2; Short=FLT-2; AltName: Full=N-sam; AltName: Full=Proto-oncogene c-Fgr; AltName: CD_antigen=CD331; Flags: Precursor
Description ..   
Protein Family: Catalytic domain of the Protein Tyrosine Kinase, Fibroblast Growth Factor Receptor 1
Comment ..   

Gene:FGFR1     Related Protein 3D Structures     More BioActivity Data..
Tested Compounds:
Description:
Title: 2-aminothiazole as a novel kinase inhibitor template. Structure-activity relationship studies toward the discovery of N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1- piperazinyl)]-2-methyl-4-pyrimidinyl]amino)]-1,3-thiazole-5-carboxamide (dasatinib, BMS-354825) as a potent pan-Src kinase inhibitor.

Abstract: 2-aminothiazole (1) was discovered as a novel Src family kinase inhibitor template through screening of our internal compound collection. Optimization through successive structure-activity relationship iterations identified analogs 2 (Dasatinib, BMS-354825) and 12m as pan-Src inhibitors with nanomolar to subnanomolar potencies in biochemical and cellular assays. Molecular modeling was used to construct a putative binding model for Lck inhibition by this class of compounds. The framework of key hydrogen-bond interactions proposed by this model was in agreement with the subsequent, published crystal structure of 2 bound to structurally similar Abl kinase. The oral efficacy of this class of inhibitors was demonstrated with 12m in inhibiting the proinflammatory cytokine IL-2 ex vivo in mice (ED50 approximately 5 mg/kg) and in reducing TNF levels in an acute murine model of inflammation (90% inhibition in LPS-induced TNFalpha production when dosed orally at 60 mg/kg, 2 h prior to LPS administration). The oral efficacy of 12m was further demonstrated in a chronic model of adjuvant arthritis in rats with established disease when administered orally at 0.3 and 3 mg/kg twice daily. Dasatinib (2) is currently in clinical trials for the treatment of chronic myelogenous leukemia.
(PMID: 17154512)
Categorized Comment
ChEMBL Assay Type: Binding

ChEMBL Assay Data Source: Scientific Literature

ChEMBL Target ID: 10266

ChEMBL Target Type: Target is a single protein chain

Result Definitions
TIDNameDescriptionHistogramTypeUnit
OutcomeThe BioAssay activity outcomeOutcome
1IC50*IC50 PubChem standard valueFloatμM
2IC50 activity commentIC50 activity commentString
3IC50 standard flagIC50 standard flagInteger
4IC50 qualifierIC50 qualifierString
5IC50 published valueIC50 published valueFloatnM
6IC50 standard valueIC50 standard valueFloatnM

* Activity Concentration.

Data Table (Concise)
Classification
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