Inhibition of ALK5
Protein kinases play a pivotal role in cell signaling, and dysregulation of many kinases has been linked to disease development. A large number of kinase inhibitors are therefore currently under investigation in clinical trials, and so far seven inhibitors have been approved as anti-cancer drugs. In addition, kinase inhibitors are widely used as specific probes to study cell signaling, but more ..
BioActive Compound: 1
Title: A systematic interaction map of validated kinase inhibitors with Ser/Thr kinases.
Abstract: Protein kinases play a pivotal role in cell signaling, and dysregulation of many kinases has been linked to disease development. A large number of kinase inhibitors are therefore currently under investigation in clinical trials, and so far seven inhibitors have been approved as anti-cancer drugs. In addition, kinase inhibitors are widely used as specific probes to study cell signaling, but systematic studies describing selectivity of these reagents across a panel of diverse kinases are largely lacking. Here we evaluated the specificity of 156 validated kinase inhibitors, including inhibitors used in clinical trials, against 60 human Ser/Thr kinases using a thermal stability shift assay. Our analysis revealed many unexpected cross-reactivities for inhibitors thought to be specific for certain targets. We also found that certain combinations of active-site residues in the ATP-binding site correlated with the detected ligand promiscuity and that some kinases are highly sensitive to inhibition using diverse chemotypes, suggesting them as preferred intervention points. Our results uncovered also inhibitor cross-reactivities that may lead to alternate clinical applications. For example, LY333'531, a PKCbeta inhibitor currently in phase III clinical trials, efficiently inhibited PIM1 kinase in our screen, a suggested target for treatment of leukemia. We determined the binding mode of this inhibitor by x-ray crystallography and in addition showed that LY333'531 induced cell death and significantly suppressed growth of leukemic cells from acute myeloid leukemia patients.
Compounds with activity <= 50uM or explicitly reported as active by ChEMBL are flagged as active in this PubChem assay presentation.
ChEMBL Target ID: 13004
Target Type: SINGLE PROTEIN
Pref Name: TGF-beta receptor type I
Synonyms: Activin A receptor type II-like protein kinase of 53kD;Activin receptor-like kinase 5;ALK-5;ALK5;Serine/threonine-protein kinase receptor R4;SKR4;TbetaR-I;TGF-beta receptor type I;TGF-beta receptor type-1;TGF-beta type I receptor;TGFR-1;Transforming growth factor-beta receptor type I;
Gene Name: ALK5 ;SKR4;TGFBR1;
Protein Accession: P36897;
Protein GI: 547777;
Organism: Homo sapiens
Tax ID: 9606
Target Classification: enzyme kinase protein kinase tkl stkr type1
Confidence: Homologous single protein target assigned
Relationship Type: Homologous protein target assigned
Categorized Comment - additional comments and annotations
* Activity Concentration.
Data Table (Concise)