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Application of a Substrate-Mediated Selection with c-Src Tyrosine Kinase to a DNA-Encoded Chemical Library.
- Source :
-
Molecules (Basel, Switzerland) [Molecules] 2019 Jul 30; Vol. 24 (15). Date of Electronic Publication: 2019 Jul 30. - Publication Year :
- 2019
-
Abstract
- As aberrant activity of protein kinases is observed in many disease states, these enzymes are common targets for therapeutics and detection of activity levels. The development of non-natural protein kinase substrates offers an approach to protein substrate competitive inhibitors, a class of kinase inhibitors with promise for improved specificity. Also, kinase activity detection approaches would benefit from substrates with improved activity and specificity. Here, we apply a substrate-mediated selection to a peptidomimetic DNA-encoded chemical library for enrichment of molecules that can be phosphorylated by the protein tyrosine kinase, c-Src. Several substrates were identified and characterized for activity. A lead compound ( SrcDEL10 ) showed both the ability to serve as a substrate and to promote ATP hydrolysis by the kinase. In inhibition assays, compounds displayed IC <subscript>50'</subscript> s ranging from of 8-100 µM. NMR analysis of SrcDEL10 bound to the c-Src:ATP complex was conducted to characterize the binding mode. An ester derivative of the lead compound demonstrated cellular activity with inhibition of Src-dependent signaling in cell culture. Together, the results show the potential for substrate-mediated selections of DNA-encoded libraries to discover molecules with functions other than simple protein binding and offer a new discovery method for development of synthetic tyrosine kinase substrates.
- Subjects :
- Adenosine Triphosphate chemistry
Antibodies, Monoclonal chemistry
DNA metabolism
Genes, Reporter
Humans
Hydrolysis
Kinetics
Luciferases genetics
Luciferases metabolism
Peptidomimetics metabolism
Phosphorylation
Protein Binding
Small Molecule Libraries metabolism
Structure-Activity Relationship
Substrate Specificity
src-Family Kinases metabolism
Combinatorial Chemistry Techniques
DNA chemistry
Peptidomimetics chemical synthesis
Small Molecule Libraries chemistry
src-Family Kinases chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 1420-3049
- Volume :
- 24
- Issue :
- 15
- Database :
- MEDLINE
- Journal :
- Molecules (Basel, Switzerland)
- Publication Type :
- Academic Journal
- Accession number :
- 31366048
- Full Text :
- https://doi.org/10.3390/molecules24152764