Protein Kinases as Drug Development Targets for Heart Disease Therapy

Abstract

Protein kinases are intimately integrated in different signal transduction pathways for the regulation of cardiac function in both health and disease. Protein kinase A (PKA), Ca2+-calmodulin-dependent protein kinase (CaMK), protein kinase C (PKC), phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) are not only involved in the control of subcellular activities for maintaining cardiac function, but also participate in the development of cardiac dysfunction in cardiac hypertrophy, diabetic cardiomyopathy, myocardial infarction, and heart failure. Although all these kinases serve as signal transducing proteins by phosphorylating different sites in cardiomyocytes, some of their effects are cardioprotective whereas others are detrimental. Such opposing effects of each signal transduction pathway seem to depend upon the duration and intensity of stimulus as well as the type of kinase isoform for each kinase. In view of the fact that most of these kinases are activated in heart disease and their inhibition has been shown to improve cardiac function, it is suggested that these kinases form excellent targets for drug development for therapy of heart disease.

KinMap: a web-based tool for interactive navigation through human kinome data

“…Finally, KinMap supports a minimalistic text input for less sophisticated annotations. For example, the following concise syntax annotates eight kinases potentially involved in cardiomyopathy [15]:…”

Mitogen-activated protein kinase signaling and its association with oxidative stress and apoptosis in lead-exposed hepatocytes

“…The mitogen‐activated protein kinases (MAPKs), a group of serine‐threonine kinases, are involved in regulating several signaling pathways that are crucial for the integration of mitogenic or apoptotic signals in cells (Papa et al, ; Yoshizumi et al, ). MAPKs regulate many important biological activities by influencing various cellular processes, namely, transcription, cell proliferation and survival, cell differentiation, inflammation, induction of apoptosis, and malignant transformation (Dhalla and Müller, ). They are classified into three major groups, the extracellular signal‐regulated kinases (ERKs), the c‐Jun N‐terminal kinases (JNKs) and the p38‐MAPK (Dhalla and Müller, ).…”

“…MAPKs regulate many important biological activities by influencing various cellular processes, namely, transcription, cell proliferation and survival, cell differentiation, inflammation, induction of apoptosis, and malignant transformation (Dhalla and Müller, ). They are classified into three major groups, the extracellular signal‐regulated kinases (ERKs), the c‐Jun N‐terminal kinases (JNKs) and the p38‐MAPK (Dhalla and Müller, ). They operate in cells through a well‐organized three‐tier module system, but with abundant cross talks between the modules ( reviewed in Manna and Stocco, ).…”

Breakthroughs in modern cancer therapy and elusive cardiotoxicity: Critical research‐practice gaps, challenges, and insights

“…For example, such genetic events noticed in cancer are also observed in autoimmune disorders, in which approximately 90% of the causal variants are non‐coding, and most map to immune cell enhancer regions . Given the central role in cellular signaling of kinases in the heart and many other organs aside from cancers, accumulating pharmacological and pathological evidence has revealed that kinases are also promising drug targets for numerous non‐oncological indications . The successful approval of tofacitinib for the treatment of arthritis is a typical example, although the exact mode of action of tofacitinib in the setting of autoimmune disease has yet to be unraveled .…”