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BioAssay: AID 271954

Inhibition of p38 kinase

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)
 
 
Active(2)
 
 
 Tested Substances
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All(2)
 
 
Active(2)
 
 
 Related BioAssays
 Related BioAssays
AID: 271954
Data Source: ChEMBL (409113)
Depositor Category: Literature, Extracted
BioAssay Version:
Deposit Date: 2010-05-25
Modify Date: 2013-11-18

Data Table ( Complete ):           Active    All
BioActive Compounds: 2
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)
Comment
Compounds with activity <= 50uM or explicitly reported as active by ChEMBL are flagged as active in this PubChem assay presentation.

Putative Target:

ChEMBL Target ID: 104697
Target Type: PROTEIN FAMILY
Pref Name: MAP kinase p38
Synonyms: CSAID-binding protein;CSBP;Cytokine suppressive anti-inflammatory drug-binding protein;MAP kinase 14;MAP kinase MXI2;MAP kinase p38 alpha;MAPK 14;MAX-interacting protein 2;Mitogen-activated protein kinase 14;Mitogen-activated protein kinase p38 alpha;SAPK2a;Stress-activated protein kinase 2a;ERK-6;Extracellular signal-regulated kinase 6;MAP kinase 12;MAP kinase p38 gamma;MAPK 12;Mitogen-activated protein kinase 12;Mitogen-activated protein kinase p38 gamma;Stress-activated protein kinase 3;MAP kinase 11;MAP kinase p38 beta;MAPK 11;Mitogen-activated protein kinase 11;Mitogen-activated protein kinase p38 beta;p38-2;p38b;SAPK2b;Stress-activated protein kinase 2b;MAP kinase 13;MAP kinase p38 delta;MAPK 13;Mitogen-activated protein kinase 13;Mitogen-activated protein kinase p38 delta;Stress-activated protein kinase 4;
Gene Name: CSBP ;CSBP1;CSBP2;CSPB1;MAPK14;MXI2;SAPK2A;ERK6 ;MAPK12;SAPK3;MAPK11;PRKM11 ;SAPK2;SAPK2B;MAPK13;PRKM13 ;SAPK4;
Protein Accession: Q16539;P53778;Q15759;O15264;
Protein GI: 2499600;2851522;134047835;6685642;
Organism: Homo sapiens
Tax ID: 9606
Target Classification: enzyme kinase protein kinase ser_thr cmgc mapk p38
Confidence: Multiple homologous protein targets may be assigned
Relationship Type: Homologous protein target assigned
Categorized Comment
ChEMBL Assay Type: Binding

ChEMBL Assay Data Source: Scientific Literature

Result Definitions
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TIDNameDescriptionHistogramTypeUnit
OutcomeThe BioAssay activity outcomeOutcome
1IC50*IC50 PubChem standard valueFloatμM
2BEIBinding Efficiency Index(nM)Float
3SEISurface Efficiency Index(nM)Float
4LELigand EfficiencyFloat
5LLELipophilic Ligand EfficiencyFloat
6IC50 activity commentIC50 activity commentString
7IC50 standard flagIC50 standard flagInteger
8IC50 qualifierIC50 qualifierString
9IC50 published valueIC50 published valueFloatnM
10IC50 standard valueIC50 standard valueFloatnM

* Activity Concentration.

Data Table (Concise)
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