Protein kinase inhibitors: structural insights into selectivity.
Protein kinases are involved in many diseases like cancer, inflammation, cardiovascular disease, and diabetes. They have become attractive target classes for drug development, making kinase inhibitors as important class of therapeutics. The success of small-molecule ATP-competitive kinase inhibitors such as Gleevec, Iressa, and Tarceva has attracted much attention in the recent past. Kinases make use of ATP for phosphorylation of a specific residue(s) on their protein substrates. More than 400 X-ray structures of about 70 different kinases are publicly available. These structures provide insights into selectivity and mechanisms of inhibition. However, prediction of binding specificity of kinase inhibitors based on structural information alone appears to be insufficient. Here, we will review these observations to gain insights into the rules that govern protein kinase inhibitor selectivity.
Thaimattam
Ram
R
Department of Molecular Modeling and Drug Design, Discovery Research, Bollaram Road, Miyapur, Hyderabad 500 049, India. ramthaimattam@drreddys.com
Banerjee
Rahul
R
Miglani
Rajni
R
Iqbal
Javed
J
D000818:Animals; D006801:Humans; D011485:Protein Binding / Q000502:physiology; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000378:metabolism* / Q000627:therapeutic use; D011494:Protein Kinases / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship
D047428:Protein Kinase Inhibitors; D011494:Protein Kinases