Disease mechanisms and emerging therapies: protein kinases and their inhibitors in myocardial disease.
Most clinically validated drugs for treating patients with cardiovascular disease target G-protein-coupled receptors (GPCRs) in the cell membrane. GPCRs engage and activate multiple intracellular signaling cascades, which are regulated by serine/threonine protein kinases. These protein kinases are cytoplasmic, more abundant than GPCRs, and have rapidly emerged as drug targets in cardiovascular diseases. One exciting potential advantage to targeting serine/threonine protein kinases rather than GPCRs is the capability of influencing more precisely the diverse biological responses that are initiated by a common GPCR. On the other hand, highly specific targeting of individual protein kinases for drug therapy presents some medicinal chemistry challenges. This concise review focuses on the biology of serine/threonine protein kinases in the cardiovascular system, discusses the current state of protein kinase inhibitor drug development for myocardial diseases, and illustrates some of the unique medicinal chemistry considerations in targeting protein kinases.
Anderson
Mark E
ME
Cardiovascular Research Center at the University of Iowa, Iowa City 52242-1081, USA. mark-e-anderson@uiowa.edu
Higgins
Linda S
LS
Schulman
Howard
H
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D009202:Cardiomyopathies / Q000188:drug therapy* / Q000201:enzymology* / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D006801:Humans; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011494:Protein Kinases / Q000145:classification / Q000187:drug effects* / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
D047428:Protein Kinase Inhibitors; D043562:Receptors, G-Protein-Coupled; D000255:Adenosine Triphosphate; D011494:Protein Kinases