Magic bullets for protein kinases.
A chemical-genetic method for the generation of target-specific protein kinase inhibitors has been developed recently. This strategy utilizes a functionally silent active-site mutation to sensitize a target kinase to inhibition by a small molecule that does not inhibit wild-type kinases. Tyrosine and serine/threonine kinases are equally amenable to the drug-sensitization approach, which has been used to generate selective inhibitors of mutant Src-family kinases, Abl-family kinases, cyclin-dependent kinases, mitogen-activated kinases, p21-activated kinases and Ca(2+)/calmodulin-dependent kinases. The designed inhibitors are specific for the sensitized kinase in a cellular background where the wild-type kinase has been inactivated. By these means, kinase-sensitization has been used systematically to generate and analyze conditional alleles of several yeast protein kinases in vivo.
Bishop
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Skaggs Institute for Chemical Biology, Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA 92037, USA.
Buzko
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Shokat
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D000818:Animals; D002352:Carrier Proteins / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D016503:Drug Delivery Systems / Q000379:methods / Q000639:trends; D015195:Drug Design; D015316:Genetic Therapy / Q000379:methods / Q000639:trends; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D016296:Mutagenesis; D011494:Protein Kinases / Q000187:drug effects / Q000235:genetics* / Q000627:therapeutic use*
D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; C015482:protein kinase modulator; D011494:Protein Kinases