A structural atlas of kinases inhibited by clinically approved drugs.
The aberrant activation of protein kinases is associated with many human diseases, most notably cancer. Due to this link between kinase deregulation and disease progression, kinases are one of the most targeted protein families for small-molecule inhibition. Within the last 15 years, the U.S. Food and Drug Administration has approved over 20 small-molecule inhibitors of protein kinases for use in the clinic. These inhibitors target the kinase active site and represent the successful hurdling by medicinal chemists of the formidable challenge posed by the high similarity among the active sites of the approximately 500 human kinases. We review the conserved structural features of kinases that are important for inhibitor binding as well as for catalysis. Many clinically approved drugs elicit selectivity by exploiting subtle variation within the kinase active site. We highlight some of the crystallographic studies on the kinase-inhibitor complexes that have provided valuable guidance for the development of these drugs as well as for future drug design efforts.
Department of Molecular and Cell Biology, University of California, Berkeley, California, USA; California Institute for Quantitative Biosciences, University of California, Berkeley, California, USA.
Qi
Q
Wang
Department of Molecular and Cell Biology, University of California, Berkeley, California, USA; California Institute for Quantitative Biosciences, University of California, Berkeley, California, USA.
Julie A
JA
Zorn
Department of Molecular and Cell Biology, University of California, Berkeley, California, USA; California Institute for Quantitative Biosciences, University of California, Berkeley, California, USA; Howard Hughes Medical Institute, University of California, Berkeley, California, USA; Department of Chemistry, University of California, Berkeley, California, USA; Physical Biosciences Division, Lawrence Berkeley National Laboratory, Berkeley, California, USA. Electronic address: kuriyan@berkeley.edu.
John
J
Kuriyan
D000255:Adenosine Triphosphate / Q000378:metabolism; D000595:Amino Acid Sequence; D055162:Biocatalysis / Q000187:drug effects; D020134:Catalytic Domain; D017124:Conserved Sequence; D006801:Humans; D008958:Models, Molecular; D009154:Mutation; D010766:Phosphorylation / Q000187:drug effects; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011494:Protein Kinases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000187:drug effects
D047428:Protein Kinase Inhibitors; D000255:Adenosine Triphosphate; D011494:Protein Kinases
Crystal structure; Drug; Inhibitor; Kinase