Therapeutic peptides targeting protein kinase: progress, challenges, and future directions, featuring cancer and cardiovascular disease

The protein kinase family is a class of enzymes that modulate the function and activity of other proteins through phosphorylation. Protein kinases are critical components of many aspects of cellular function including signal transduction, cellular metabolism, transcription, proliferation, division, translation, cell-cycle progression, biosynthesis, movement, and survival. As phosphorylation by protein kinases is a central theme in biological systems catalyzing a great variety of critical biological reactions, aberrant expression or function of protein kinases can have major implications on cell health and viability and has been linked to a variety of pathological conditions, such as neurodegeneration, inflammation, autoimmunity, cardiovascular disease, and cancer. Furthermore, protein kinases are the second most utilized group of drug targets, after the G-protein-coupled receptors. The approval of the first protein kinase inhibitor (PKI) for clinical use occurred in 1995 for fasudil, a RhoA/Rho kinase inhibitor used for treating cerebral vasospasms, and since then many kinase inhibitors have received Food and Drug Administration approval. However, the majority of these inhibitors are small molecules that target the adenosine triphosphate (ATP)-binding pocket that is highly conserved across human kinases, making it difficult to develop selective kinase inhibitors. In addition, patients treated with small-molecule kinase inhibitors may develop resistance to such drugs due to high mutation rates within the ATP-binding site. Peptides have emerged as selective and effective tools to modulate protein kinase activity. However, peptides may be limited by rapid proteolysis and inadequate membrane permeability. Peptidomimetic (modified peptide) analogs, which offer greater stability, selectivity and bioavailability compared to linear peptides, are a promising class of therapeutics targeting protein kinases. This chapter provides an overview of the development and application of peptide and peptidomimetic PKIs, as well as their limitations and opportunities as therapeutic agents.