Strategies for the design of potent and selective kinase inhibitors.
The characterisation of the human kinome in recent years has resulted in the emergence of numerous kinase drug targets in a variety of therapeutic areas. Through the elucidation of the sequence and structural composition of kinase active sites, coupled with the solution of numerous ATP competitive ligand complex structures, significant advances have been made in developing inhibitors that are highly selective. This has shown to be the case not only for kinases that are divergent in primary structure, but also for isoforms with highly conserved structure and ATP binding sites. Here we review the methods employed in the generation of selective inhibitors and describe several successful examples of the design of highly potent and selective kinase ATP competitive ligands. We also describe examples where an alternate approach to selectivity was used. These include the use of small molecules to sequester kinases in inactive conformations, and to block phospho-transferase activity by preventing substrate docking and recruitment. Substrate recruitment sites are promising from a structure based design perspective as they contain features unique to individual protein kinases.
McInnes
Campbell
C
Cyclacel Ltd., James Lindsay Place, Dundee DD1 5JJ, Scotland, UK. cmcinnes@cyclacel.com
Fischer
Peter M
PM
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001549:Benzamides; D001665:Binding Sites; D016203:CDC2 Protein Kinase / Q000037:antagonists & inhibitors / Q000737:chemistry; D042846:CDC2-CDC28 Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry; D018360:Crystallography, X-Ray; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry; D051357:Cyclin-Dependent Kinase 2; D015195:Drug Design; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D006801:Humans; D000068877:Imatinib Mesylate; D047908:Intracellular Signaling Peptides and Proteins / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D048057:Mitogen-Activated Protein Kinase 10 / Q000037:antagonists & inhibitors / Q000737:chemistry; D010766:Phosphorylation; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry
D001549:Benzamides; D047908:Intracellular Signaling Peptides and Proteins; D010879:Piperazines; D011743:Pyrimidines; C015482:protein kinase modulator; D000068877:Imatinib Mesylate; D000255:Adenosine Triphosphate; D048057:Mitogen-Activated Protein Kinase 10; D066246:ErbB Receptors; D017868:Cyclic AMP-Dependent Protein Kinases; D016203:CDC2 Protein Kinase; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D048051:p38 Mitogen-Activated Protein Kinases