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)

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
Description: Mitogen-activated protein kinase 11
Organism: Homo sapiens
Tax ID: 9606
Confidence: Multiple homologous protein targets may be assigned
Relationship Type: Homologous protein target assigned
ChEMBL target type: Target is a group of closely related proteins

ChEMBL Target ID: 104697
Target Type: PROTEIN FAMILY
Pref Name: MAP kinase p38
Description: Mitogen-activated protein kinase 11
Organism: Homo sapiens
Tax ID: 9606
Confidence: Multiple homologous protein targets may be assigned
Relationship Type: Homologous protein target assigned
ChEMBL target type: Target is a group of closely related proteins

ChEMBL Target ID: 104697
Target Type: PROTEIN FAMILY
Pref Name: MAP kinase p38
Description: Mitogen-activated protein kinase 11
Organism: Homo sapiens
Tax ID: 9606
Confidence: Multiple homologous protein targets may be assigned
Relationship Type: Homologous protein target assigned
ChEMBL target type: Target is a group of closely related proteins

ChEMBL Target ID: 104697
Target Type: PROTEIN FAMILY
Pref Name: MAP kinase p38
Description: Mitogen-activated protein kinase 11
Organism: Homo sapiens
Tax ID: 9606
Confidence: Multiple homologous protein targets may be assigned
Relationship Type: Homologous protein target assigned
ChEMBL target type: Target is a group of closely related proteins

ChEMBL Target ID: 104697
Target Type: PROTEIN FAMILY
Pref Name: MAP kinase p38
Description: Mitogen-activated protein kinase 12
Organism: Homo sapiens
Tax ID: 9606
Confidence: Multiple homologous protein targets may be assigned
Relationship Type: Homologous protein target assigned
ChEMBL target type: Target is a group of closely related proteins

ChEMBL Target ID: 104697
Target Type: PROTEIN FAMILY
Pref Name: MAP kinase p38
Description: Mitogen-activated protein kinase 12
Organism: Homo sapiens
Tax ID: 9606
Confidence: Multiple homologous protein targets may be assigned
Relationship Type: Homologous protein target assigned
ChEMBL target type: Target is a group of closely related proteins

ChEMBL Target ID: 104697
Target Type: PROTEIN FAMILY
Pref Name: MAP kinase p38
Description: Mitogen-activated protein kinase 12
Organism: Homo sapiens
Tax ID: 9606
Confidence: Multiple homologous protein targets may be assigned
Relationship Type: Homologous protein target assigned
ChEMBL target type: Target is a group of closely related proteins

ChEMBL Target ID: 104697
Target Type: PROTEIN FAMILY
Pref Name: MAP kinase p38
Description: Mitogen-activated protein kinase 12
Organism: Homo sapiens
Tax ID: 9606
Confidence: Multiple homologous protein targets may be assigned
Relationship Type: Homologous protein target assigned
ChEMBL target type: Target is a group of closely related proteins

ChEMBL Target ID: 104697
Target Type: PROTEIN FAMILY
Pref Name: MAP kinase p38
Description: Mitogen-activated protein kinase 13
Organism: Homo sapiens
Tax ID: 9606
Confidence: Multiple homologous protein targets may be assigned
Relationship Type: Homologous protein target assigned
ChEMBL target type: Target is a group of closely related proteins

ChEMBL Target ID: 104697
Target Type: PROTEIN FAMILY
Pref Name: MAP kinase p38
Description: Mitogen-activated protein kinase 13
Organism: Homo sapiens
Tax ID: 9606
Confidence: Multiple homologous protein targets may be assigned
Relationship Type: Homologous protein target assigned
ChEMBL target type: Target is a group of closely related proteins

ChEMBL Target ID: 104697
Target Type: PROTEIN FAMILY
Pref Name: MAP kinase p38
Description: Mitogen-activated protein kinase 13
Organism: Homo sapiens
Tax ID: 9606
Confidence: Multiple homologous protein targets may be assigned
Relationship Type: Homologous protein target assigned
ChEMBL target type: Target is a group of closely related proteins

ChEMBL Target ID: 104697
Target Type: PROTEIN FAMILY
Pref Name: MAP kinase p38
Description: Mitogen-activated protein kinase 13
Organism: Homo sapiens
Tax ID: 9606
Confidence: Multiple homologous protein targets may be assigned
Relationship Type: Homologous protein target assigned
ChEMBL target type: Target is a group of closely related proteins

ChEMBL Target ID: 104697
Target Type: PROTEIN FAMILY
Pref Name: MAP kinase p38
Description: Mitogen-activated protein kinase 14
Organism: Homo sapiens
Tax ID: 9606
Confidence: Multiple homologous protein targets may be assigned
Relationship Type: Homologous protein target assigned
ChEMBL target type: Target is a group of closely related proteins

ChEMBL Target ID: 104697
Target Type: PROTEIN FAMILY
Pref Name: MAP kinase p38
Description: Mitogen-activated protein kinase 14
Organism: Homo sapiens
Tax ID: 9606
Confidence: Multiple homologous protein targets may be assigned
Relationship Type: Homologous protein target assigned
ChEMBL target type: Target is a group of closely related proteins

ChEMBL Target ID: 104697
Target Type: PROTEIN FAMILY
Pref Name: MAP kinase p38
Description: Mitogen-activated protein kinase 14
Organism: Homo sapiens
Tax ID: 9606
Confidence: Multiple homologous protein targets may be assigned
Relationship Type: Homologous protein target assigned
ChEMBL target type: Target is a group of closely related proteins

ChEMBL Target ID: 104697
Target Type: PROTEIN FAMILY
Pref Name: MAP kinase p38
Description: Mitogen-activated protein kinase 14
Organism: Homo sapiens
Tax ID: 9606
Confidence: Multiple homologous protein targets may be assigned
Relationship Type: Homologous protein target assigned
ChEMBL target type: Target is a group of closely related proteins

ChEMBL Assay Type: Binding

ChEMBL Assay Data Source: Scientific Literature