An Update on Protein Kinases as Therapeutic Targets-Part I: Protein Kinase C Activation and Its Role in Cancer and Cardiovascular Diseases

Abstract

Protein kinases are one of the most significant drug targets in the human proteome, historically harnessed for the treatment of cancer, cardiovascular disease, and a growing number of other conditions, including autoimmune and inflammatory processes. Since the approval of the first kinase inhibitors in the late 1990s and early 2000s, the field has grown exponentially, comprising 98 approved therapeutics to date, 37 of which were approved between 2016 and 2021. While many of these small-molecule protein kinase inhibitors that interact orthosterically with the protein kinase ATP binding pocket have been massively successful for oncological indications, their poor selectively for protein kinase isozymes have limited them due to toxicities in their application to other disease spaces. Thus, recent attention has turned to the use of alternative allosteric binding mechanisms and improved drug platforms such as modified peptides to design protein kinase modulators with enhanced selectivity and other pharmacological properties. Herein we review the role of different protein kinase C (PKC) isoforms in cancer and cardiovascular disease, with particular attention to PKC-family inhibitors. We discuss translational examples and carefully consider the advantages and limitations of each compound (Part I). We also discuss the recent advances in the field of protein kinase modulators, leverage molecular docking to model inhibitor-kinase interactions, and propose mechanisms of action that will aid in the design of next-generation protein kinase modulators (Part II).

Keywords: allosteric; cancer; cardiovascular disease; peptides; protein kinase; protein kinase C (PKC).

Figure 1

PKC isozyme diversity. (A) The human kinome (adapted from www.cellsignal.com/reference/kinase) phylogeny is extensive, and the PKC family is one member of the AGC superfamily (bottom right), with three groups of conventional, novel, and atypical PKC isozymes. (B) PKC isozymes are homologous but contain a distinct set of structural domains responsible for their diverse functions and interactions with second messengers and other binding partners. All PKC family members are constituted by four conserved domains (C1–C4) separated by a hinge region. The pseudo-substrate site (PS) keeps the protein in its inactive form. Second messengers are indicated on the right side of the picture. BioRender.com was used to generate this figure.

Figure 2

PKC maturation, activation, and cytosolic fate. The open PKC matures via a priming process involving three critical phosphorylation events, which is facilitated by chaperone complex proteins. PKC adopts a closed, autoinhibited, conformation in which the pseudo-substrate (PS) domain is trapped in the substrate-binding site, and the primed enzyme localizes to the cytosol. The closed mature PKC in the cytosol is then activated by second messengers and scaffold proteins that mediate the target specificity of the kinase. The cytosolic survival of the species and the fate of the protein are determined by other scaffolds and post-translational modifications that govern downregulation and degradation reactions. BioRender.com was used to generate this figure.