Bivalent Inhibitors of c-Src Tyrosine Kinase That Bind a Regulatory Domain.
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.
Departments of Medicinal Chemistry and ‡Chemistry, University of Michigan , Ann Arbor, Michigan 48109, United States.
Taylor K
TK
Johnson
Departments of Medicinal Chemistry and ‡Chemistry, University of Michigan , Ann Arbor, Michigan 48109, United States.
Matthew B
MB
Soellner
D000255:Adenosine Triphosphate / Q000378:metabolism; D000480:Alkynes / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D000595:Amino Acid Sequence; D001667:Binding, Competitive; D000081247:CSK Tyrosine-Protein Kinase; D008958:Models, Molecular; D011485:Protein Binding; D000072417:Protein Domains; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D017386:Sequence Homology, Amino Acid; D013379:Substrate Specificity; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism
D000480:Alkynes; D047428:Protein Kinase Inhibitors; D000255:Adenosine Triphosphate; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases