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

Content Provider	Royal Society of Chemistry (RSC)
Author	Perera, B. Gayani K. Maly, Dustin J. Hill, Zachary B.
Copyright Year	2011
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 enzymeO6-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.
Starting Page	447
Ending Page	456
Page Count	10
File Format	HTM / HTML PDF
ISSN	1742206X
Volume Number	7
Issue Number	2
Journal	Molecular BioSystems
DOI	10.1039/c0mb00108b
Language	English
Publisher	Royal Society of Chemistry
Access Restriction	Open
Subject Keyword	Tyrosine SH3 domain SRC Ligand Kinase Determinant Enzyme inhibitor ABL DNA repair Protein
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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