Inhibitors of Protein Kinase Signaling Pathways Emerging Therapies for Cardiovascular Disease Thomas Force, MD; Keisuke Kuida, MD; Mark Namchuk, PhD; Keykavous Parang, PhD; John M. Kyriakis, PhD Abstract—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. (Circulation. 2004;109:1196-1205.) Key Words: drugs  kinases  pharmacology  inhibitors A consensus is emerging that protein kinase modulators will be effective treatments for a variety of diseases. 1 However, protein kinases were initially thought to be unsuit- able drug targets, in large part because of what was perceived to be an unfavorably high degree of structural conservation within key domains of all protein kinases. Because binding of ATP to kinases is essential for kinase activity and properties of the protein kinase ATP-binding pocket were well under- stood, agents targeting the ATP pocket were the logical first choice for drug development. However, the structural con- servation of protein kinase ATP binding sites and the pres- ence of more than 500 protein kinases in the human genome 2 led to the belief that highly selective small-molecule protein kinase inhibitors targeting the ATP pocket would be difficult to generate. As will be discussed below, the development and characterization of inhibitors of the p38 mitogen-activated protein kinases (MAPKs) indicated that this initial belief was misguided. A second argument against targeting protein kinases for drug development was the observation that modulation of a protein kinase could in one system prove beneficial, while proving deleterious in another. As an ex- treme example of this, inhibiting a protein kinase required for triggering programmed cell death could reduce ischemia- induced cell death in terminally differentiated cardiomyo- cytes but might also favor tumor promotion in other organs or cell types. Finally, toxicity with long-term use was a concern. Thus, inhibiting a protein kinase that is dysregulated in one organ in a particular disease state may prove harmful to other systems in which that same protein kinase is not dysregulated but instead serves essential functions. For example, inhibiting the cell-surface HER2 tyrosine kinase receptor with the monoclonal antibody trastuzumab (Herceptin, Genentech) in patients with breast cancers overexpressing that receptor has produced strikingly beneficial results, but it has come at the expense of severe cardiac dysfunction in some women receiving the therapy, suggesting a critical role for this receptor in cardiomyocyte survival. 3 All of the above concerns being noted, the “proof of principle” of the tremendous therapeutic potential of small- molecule inhibitors of protein kinases came with the discov- 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.). Drs Namchuck and Kuida are employees of and Dr Force receives financial support for his laboratory from Vertex Pharmaceuticals, Inc, which produces small-molecule inhibitors of protein kinases, are the subject of this article. Additional material may be found in the Data Supplement with the online-only version of this article at http://www.circulationaha.org. 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@tufts-nemc.org © 2004 American Heart Association, Inc. Circulation is available at http://www.circulationaha.org DOI: 10.1161/01.CIR.0000118538.21306.A9 1196 From Bench to Bedside by guest on July 6, 2015 http://circ.ahajournals.org/ Downloaded from