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Bivalent inhibitors of the tyrosine kinases ABL and SRC: Determinants of potency and selectivity

Content Provider	PubMed Central
Author	Hill, Zachary B. Perera, B. Gayani K. Maly, Dustin J.
Abstract	We recently reported a chemical genetic method for generating bivalent inhibitors of protein kinases. This method relies on the use of the DNA repair enzyme O 6-alkylguanine-DNA alkyltransferase (AGT) to display an ATP-competitive inhibitor and a ligand that targets a secondary binding domain. With this method potent and selective inhibitors of the tyrosine kinases SRC and ABL were identified. Here, we dissect the molecular determinants of the potency and selectivity of these bivalent ligands. Systematic analysis of ATP-competitive inhibitors with varying linker lengths revealed that SRC and ABL have differential sensitivities to ligand presentation. Generation of bivalent constructs that contain ligands with differential affinities for the ATP-binding sites and SH3 domains of SRC and ABL demonstrated the modular nature of inhibitors based on the AGT scaffold. Furthermore, these studies revealed that the interaction between the SH3 domain ligand and the kinase SH3 domain is the major selectivity determinant amongst closely-related tyrosine kinases. Finally, the potency of bivalent inhibitors against distinct phospho-isoforms of SRC was determined. Overall, these results provide insight into how individual ligands can be modified to provide more potent and selective bivalent inhibitors of protein kinases.
Related Links	http://dx.doi.org/10.1039/c0mb00108b
Ending Page	456
Page Count	10
Starting Page	447
File Format	PDF
ISSN	1742206X
e-ISSN	17422051
Journal	Molecular Biosystems
Issue Number	2
Volume Number	7
Language	English
Publisher Date	2011-01-01
Access Restriction	Open
Subject Keyword	Biotechnology Molecular Biology Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Molecular Biology Biotechnology

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Bivalent inhibitors of the tyrosine kinases ABL and SRC: determinants of potency and selectivity

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Bivalent inhibitors of the tyrosine kinases ABL and SRC: Determinants of potency and selectivity