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

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 w...

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Bibliographic Details
Published in:	International journal of molecular sciences 2023-12, Vol.24 (24), p.17504
Main Authors:	Zerihun, Mulate, Rubin, Samuel J S, Silnitsky, Shmuel, Qvit, Nir
Format:	Article
Language:	eng
Subjects:	Adenosine triphosphate allosteric Allosteric Regulation Amino acids Binding sites Cardiovascular Diseases Drug therapy FDA approval Federal regulation Homeostasis Humans Kinases modified peptides Molecular Docking Simulation Neoplasms Peptides Peptides - pharmacology peptidomimetics Pharmaceutical industry Phosphorylation Protein Kinase C Protein Kinase Inhibitors - chemistry Protein Kinase Inhibitors - pharmacology Protein Kinase Inhibitors - therapeutic use Proteins Toxicity Yeast
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Summary:	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.
ISSN:	1422-0067 1661-6596 1422-0067