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 ..
BioActive Compounds: 2
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.
Compounds with activity <= 50uM or explicitly reported as active by ChEMBL are flagged as active in this PubChem assay presentation.
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 cmgc mapk p38
Confidence: Multiple homologous protein targets may be assigned
Relationship Type: Homologous protein target assigned
Categorized Comment - additional comments and annotations
* Activity Concentration.
Data Table (Concise)