doi: 10.1161/01.CIR.0000118538.21306.A9
(Circulation. 2004;109:1196-1205.)
© 2004 American Heart Association, Inc.
From Bench to Bedside |
Inhibitors of Protein Kinase Signaling Pathways
Emerging Therapies for Cardiovascular Disease
From the Molecular Cardiology Research Institute, Tufts-New England Medical Center and Tufts University School of Medicine, Boston, Mass (T.F., J.M.K.); Vertex Pharmaceuticals, Inc, Cambridge, Mass (K.K., M.N.); and the Department of Biomedical Sciences, University of Rhode Island, Kingston (K.P.).
Correspondence to Thomas Force, MD, Molecular Cardiology Research Institute, Tufts-New England Medical Center, 750 Washington St, Box 8486, Boston, MA 02111. E-mail tforce{at}tufts-nemc.org
Protein kinases are enzymes that covalently modify proteins by attaching phosphate groups (from ATP) to serine, threonine, and/or tyrosine residues. In so doing, the functional properties of the protein kinase’s substrates are modified. Protein kinases transduce signals from the cell membrane into the interior of the cell. Such signals include not only those arising from ligand-receptor interactions but also environmental perturbations such as when the membrane undergoes mechanical deformation (ie, cell stretch or shear stress). Ultimately, the activation of signaling pathways that use protein kinases often culminates in the reprogramming of gene expression through the direct regulation of transcription factors or through the regulation of mRNA stability or protein translation. Protein kinases regulate most aspects of normal cellular function. The pathophysiological dysfunction of protein kinase signaling pathways underlies the molecular basis of many cancers and of several manifestations of cardiovascular disease, such as hypertrophy and other types of left ventricular remodeling, ischemia/reperfusion injury, angiogenesis, and atherogenesis. Given their roles in such a wide variety of disease states, protein kinases are rapidly becoming extremely attractive targets for drug discovery, probably second only to heterotrimeric G protein-coupled receptors (eg, angiotensin II). Here, we will review the reasons for this explosion in interest in inhibitors of protein kinases and will describe the process of identifying novel drugs directed against kinases. We will specifically focus on disease states for which drug development has proceeded to the point of clinical or advanced preclinical studies.
Key Words: drugs • kinases • pharmacology • inhibitors
This article has been cited by other articles:
 |
|
 |
|
  Direct Inhibition of {delta}-Protein Kinase C Enzy Intracoronary KAI-9803 as an Adjunct to Primary Percutaneous Coronary Intervention for Acute ST-Segment Elevation Myocardial Infarction Circulation, February 19, 2008; 117(7): 886 - 896. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. M. Wilson and J. T. Willerson Myocardial Revascularization with Percutaneous Devices Card. Surg. Adult, January 1, 2008; 3(2008): 573 - 598. [Full Text]
|
|
|
|
 |
|
 X.-L. Niu, J. Li, Z. S. Hakim, M. Rojas, M. S. Runge, and N. R. Madamanchi Leukocyte Antigen-related Deficiency Enhances Insulin-like Growth Factor-1 Signaling in Vascular Smooth Muscle Cells and Promotes Neointima Formation in Response to Vascular Injury J. Biol. Chem., July 6, 2007; 282(27): 19808 - 19819. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. DAVIS, F. S. WYLLIE, M. J. ROKICKI, M. C. BAGLEY, and D. KIPLING The Role of Cellular Senescence in Werner Syndrome: Toward Therapeutic Intervention in Human Premature Aging Ann. N.Y. Acad. Sci., April 1, 2007; 1100(1): 455 - 469. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Wang and H. G. Dohlman Regulation of G Protein and Mitogen-Activated Protein Kinase Signaling by Ubiquitination: Insights From Model Organisms Circ. Res., December 8, 2006; 99(12): 1305 - 1314. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Bellahcene, S. Jacquet, X. B. Cao, M. Tanno, R. S. Haworth, J. Layland, A. M. Kabir, M. Gaestel, R. J. Davis, R. A. Flavell, et al. Activation of p38 Mitogen-Activated Protein Kinase Contributes to the Early Cardiodepressant Action of Tumor Necrosis Factor J. Am. Coll. Cardiol., August 1, 2006; 48(3): 545 - 555. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. W.M. Schellings, M. Baumann, R. E.W. van Leeuwen, R. F.J.J. Duisters, S. H.P. Janssen, B. Schroen, C. J. Peutz-Kootstra, S. Heymans, and Y. M. Pinto Imatinib Attenuates End-Organ Damage in Hypertensive Homozygous TGR(mRen2)27 Rats Hypertension, March 1, 2006; 47(3): 467 - 474. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Toth, P. Nickson, L. L. Qin, and P. Erhardt Differential Regulation of Cardiomyocyte Survival and Hypertrophy by MDM2, an E3 Ubiquitin Ligase J. Biol. Chem., February 10, 2006; 281(6): 3679 - 3689. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Munzel, U. Muhlhauser, W.-H. Zimmermann, M. Didie, K. Schneiderbanger, P. Schubert, S. Engmann, T. Eschenhagen, and O. Zolk Endothelin-1 and isoprenaline co-stimulation causes contractile failure which is partially reversed by MEK inhibition Cardiovasc Res, December 1, 2005; 68(3): 464 - 474. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. P D Wheeler-Jones Cell signalling in the cardiovascular system: an overview Heart, October 1, 2005; 91(10): 1366 - 1374. [Full Text] [PDF]
|
|
|
|
 |
|
 G. Ramesh and W. B. Reeves p38 MAP kinase inhibition ameliorates cisplatin nephrotoxicity in mice Am J Physiol Renal Physiol, July 1, 2005; 289(1): F166 - F174. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Ignjatovic, S. Stanisavljevic, V. Brovkovych, R. A. Skidgel, and E. G. Erdos Kinin B1 Receptors Stimulate Nitric Oxide Production in Endothelial Cells: Signaling Pathways Activated by Angiotensin I-Converting Enzyme Inhibitors and Peptide Ligands Mol. Pharmacol., November 1, 2004; 66(5): 1310 - 1316. [Abstract] [Full Text] [PDF]
|
|