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BioAssay: AID 507547

Inhibition of GRK4 at 1 uM after 60 mins by FRET assay in presence of 10 uM ATP

The clinical success of multitargeted kinase inhibitors has stimulated efforts to identify promiscuous drugs with optimal selectivity profiles. It remains unclear to what extent such drugs can be rationally designed, particularly for combinations of targets that are structurally divergent. Here we report the systematic discovery of molecules that potently inhibit both tyrosine kinases and more ..
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 Tested Compounds
 Tested Compounds
All(7)
 
 
Unspecified(7)
 
 
 Tested Substances
 Tested Substances
All(7)
 
 
Unspecified(7)
 
 
 Related BioAssays
 Related BioAssays
AID: 507547
Data Source: ChEMBL (655396)
Depositor Category: Literature, Extracted
BioAssay Version:
Deposit Date: 2011-09-17
Modify Date: 2014-08-24

Data Table ( Complete ):           View All Data
Tested Compounds:
Description:
Title: Targeted polypharmacology: discovery of dual inhibitors of tyrosine and phosphoinositide kinases.

Abstract: The clinical success of multitargeted kinase inhibitors has stimulated efforts to identify promiscuous drugs with optimal selectivity profiles. It remains unclear to what extent such drugs can be rationally designed, particularly for combinations of targets that are structurally divergent. Here we report the systematic discovery of molecules that potently inhibit both tyrosine kinases and phosphatidylinositol-3-OH kinases, two protein families that are among the most intensely pursued cancer drug targets. Through iterative chemical synthesis, X-ray crystallography and kinome-level biochemical profiling, we identified compounds that inhibit a spectrum of new target combinations in these two families. Crystal structures revealed that the dual selectivity of these molecules is controlled by a hydrophobic pocket conserved in both enzyme classes and accessible through a rotatable bond in the drug skeleton. We show that one compound, PP121, blocks the proliferation of tumor cells by direct inhibition of oncogenic tyrosine kinases and phosphatidylinositol-3-OH kinases. These molecules demonstrate the feasibility of accessing a chemical space that intersects two families of oncogenes.
(PMID: 18849971)
Comment
Putative Target:

ChEMBL Target ID: 101584
Target Type: SINGLE PROTEIN
Pref Name: G protein-coupled receptor kinase 4
Synonyms: G protein-coupled receptor kinase 4;G protein-coupled receptor kinase GRK4;ITI1;
Gene Name: GPRK2L ;GPRK4;GRK4;
Protein Accession: P32298;
Protein GI: 143811400;
Organism: Homo sapiens
Tax ID: 9606
Target Classification: enzyme kinase protein kinase agc grk grk
Confidence: Homologous single protein target assigned
Relationship Type: Homologous protein target assigned
Categorized Comment - additional comments and annotations
From BioAssay Depositor:
Assay Type: Binding
Assay Data Source: Scientific Literature
Result Definitions
TIDNameDescriptionHistogramTypeUnit
OutcomeThe BioAssay activity outcomeOutcome
1Inhibition activity commentInhibition activity commentString
2Inhibition standard flagInhibition standard flagInteger
3Inhibition qualifierInhibition qualifierString
4Inhibition published valueInhibition published valueFloat%
5Inhibition standard valueInhibition standard valueFloat%

Data Table (Concise)
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