1. Bivalent Inhibitors of c-Src Tyrosine Kinase That Bind a Regulatory Domain
- Author
-
Matthew B. Soellner and Taylor K. Johnson
- Subjects
0301 basic medicine ,Models, Molecular ,Protein domain ,Biomedical Engineering ,Pharmaceutical Science ,Bioengineering ,Plasma protein binding ,010402 general chemistry ,01 natural sciences ,Binding, Competitive ,Bivalent (genetics) ,Article ,Substrate Specificity ,CSK Tyrosine-Protein Kinase ,03 medical and health sciences ,Adenosine Triphosphate ,Protein Domains ,C-src tyrosine kinase ,Amino Acid Sequence ,Peptide sequence ,Protein Kinase Inhibitors ,Pharmacology ,chemistry.chemical_classification ,Sequence Homology, Amino Acid ,Chemistry ,Kinase ,Organic Chemistry ,0104 chemical sciences ,Amino acid ,030104 developmental biology ,src-Family Kinases ,Biochemistry ,Alkynes ,Selectivity ,Biotechnology ,Protein Binding - Abstract
We have developed a general methodology to produce bivalent kinase inhibitors for c-Src that interact with the SH2 and ATP binding pockets. Our approach led to a highly selective bivalent inhibitor of c-Src. We demonstrate impressive selectivity for c-Src over homologous kinases. Exploration of the unexpected high level of selectivity yielded insight into the inherent flexibility of homologous kinases. Finally, we demonstrate that our methodology is modular and both the ATP-competitive fragment and conjugation chemistry can be swapped.
- Published
- 2016