The Human Kinome and Kinase Inhibition

Abstract

Protein and lipid kinases play key regulatory roles in a number of biological processes. Unsurprisingly, activating mutations in kinases have been linked to a number of disorders and diseases, most notably cancers. Thus, kinases have emerged as promising clinical targets. There are more than 500 human protein kinases and about 20 lipid kinases. Most protein kinases share a highly conserved domain, the eukaryotic protein kinase (ePK) domain, which contains the ATP and substrate‐binding sites. Many inhibitors in clinical use bind to the highly conserved ATP binding site. For this reason, many kinase inhibitors are not exclusively selective for their intended targets. Furthermore, despite the current interest in kinase inhibitors, very few kinases implicated in disease have validated inhibitors. This unit describes the human kinome, ePK structure, and types of kinase inhibitors, focusing on methods to identify potent and selective kinase inhibitors. Curr. Protoc. Pharmacol. 60:2.9.1‐2.9.14. © 2013 by John Wiley & Sons, Inc.

Coral: Clear and Customizable Visualization of Human Kinome Data

“…These proteins have been implicated in a variety of diseases including pathological hypertrophy (Heineke and Molkentin, 2006; Vlahos et al, 2003), rheumatoid arthritis (Gaestel et al, 2009; Patterson et al, 2014), and cancer (Fleuren et al, 2016; Ventura and Nebreda, 2006). As a result, protein kinases are common candidates for drug targets and are increasingly the focus of large-scale studies (Cohen, 2002; Cohen and Alessi, 2013; Duong-Ly and Peterson, 2013; Hu et al, 2017; Li et al, 2016; Wu et al, 2016). High-throughput approaches to study kinase abundance and activity–including proteomics, genomics, and kinase profiling screens–have created a need to visualize and interpret results in the greater context of the human kinome.…”

Advances in Phos-tag-based methodologies for separation and detection of the phosphoproteome

“…Recently, techniques for detecting the phosphorylation of proteins have received a great deal of attention because they can be used to screen for targets for molecular anticancer drugs [5]. Therefore, the development of highly sensitive and specific methods for the comprehensive analysis of protein phosphorylation profiles in living organisms is of the utmost importance.…”

“…Covalent bonding of negatively charged phosphate groups to proteins causes their conformations to change and modifies their properties, resulting in dynamic control of enzymatic activity, localization, and complex formation with other proteins [2,3]. In the human body, the phosphorylation of proteins is reversibly regulated by 518 protein kinase genes [4,5] and 298 protein phosphatase genes [6]. A complicated and varied network of kinases and phosphatases is involved in the rapid and accurate regulation of protein phosphorylation, which is required for several fundamental and vital functions of cells.…”

A High-Throughput Radiometric Kinase Assay

“…The human kinome encodes 518 protein kinases that regulate a number of processes including cell growth, proliferation, apoptosis, metabolism, and differentiation (1). Even though these signaling molecules are often deregulated in diseases such as cancer, few of the human kinases have approved inhibitors.…”

“…These approaches may not yield identical results because, for example, compounds can bind a kinase but not inhibit its catalytic activity. We recently reviewed various kinase assays that fall into these two classes (1) and both types of assays have been used in recent large-scale screens of small molecule libraries against collections of recombinant kinases (3–6). …”