An Update on Protein Kinases as Therapeutic Targets—Part II: Peptides as Allosteric Protein Kinase C Modulators Targeting Protein–Protein Interactions

Abstract

Human protein kinases are highly-sought-after drug targets, historically harnessed for treating cancer, cardiovascular disease, and an increasing number of autoimmune and inflammatory conditions. Most current treatments involve small molecule protein kinase inhibitors that interact orthosterically with the protein kinase ATP-binding pocket. As a result, these compounds are often poorly selective and highly toxic. Part I of this series reviews the role of PKC isoforms in various human diseases, featuring cancer and cardiovascular disease, as well as translational examples of PKC modulation applied to human health and disease. In the present Part II, we discuss alternative allosteric binding mechanisms for targeting PKC, as well as novel drug platforms, such as modified peptides. A major goal is to design protein kinase modulators with enhanced selectivity and improved pharmacological properties. To this end, we use molecular docking analysis to predict the mechanisms of action for inhibitor–kinase interactions that can facilitate the development of next-generation PKC modulators.

Kinase Inhibitors and Kinase-Targeted Cancer Therapies: Recent Advances and Future Perspectives

“…It should be noted that some allosteric inhibitors are also believed to act on PPI sites, but they inhibit kinase activity, while PKIIs inhibit the interaction between kinases and substrates [172]. Unlike small molecules, peptides exhibit more flexible conformations, higher selectivity, and lower costs than antibodies, making them ideal candidates for inhibiting PPIs [19], as shown in Figure 3c. Short linear peptides, in particular, have advantages in improving drug properties and limiting toxicity.…”

“…Through computer analysis, Mallick et al identified the key TrkA-binding peptide sequence of NGF and designed a hybrid peptide candidate that blocks the interaction between NGF and TrkA, which showed potential in the treatment of ameloblastoma [176]. Mulate et al used AlphaFold to identify various peptides targeting PKC [19]. It is expected that more peptidebased compounds will enter development and clinical research as PKIIs.…”

“…On the other hand, protein kinase interactors build upon the concept of protein-protein interaction (PPI) inhibitors, mainly disrupting the interaction between kinases and substrates without affecting enzymatic activity [18]. Peptides are considered promising candidates for protein kinase interactors due to their more flexible conformations and higher selectivity [19]. These emerging strategies show promise in developing new targets and overcoming drug-resistant mutations, with some already progressing to clinical trials.…”