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An Update on Protein Kinases as Therapeutic Targets-Part I: Protein Kinase C Activation and Its Role in Cancer and
Shmuel Silnitsky1, Samuel J S Rubin2, Mulate Zerihun1
1The Azrieli Faculty of Medicine in the Galilee, Bar-Ilan University, Henrietta Szold St. 8, Safed 1311502, Israel.
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).
Insights
Protein kinase inhibitors are crucial for treating cancer and other diseases. New allosteric and peptide-based drugs offer improved selectivity and fewer side effects compared to traditional kinase inhibitors.
Area of Science:
- Biochemistry and Pharmacology
- Drug Discovery and Development
Background:
- Protein kinases are vital drug targets, with numerous inhibitors approved for cancer and other diseases.
- Traditional orthosteric kinase inhibitors face challenges with selectivity, leading to toxicities in non-oncological applications.
- The field has seen significant growth, with 37 new kinase inhibitors approved between 2016 and 2021.
Purpose of the Study:
- To review the role of protein kinase C (PKC) isoforms in cancer and cardiovascular disease.
- To discuss the advantages and limitations of current PKC-family inhibitors.
- To explore advances in protein kinase modulator design, including allosteric mechanisms and modified peptides.
Main Methods:
- Review of existing literature on protein kinase C isoforms and their inhibitors.
- Discussion of translational examples of PKC inhibitors in disease treatment.
- Utilizing molecular docking to model inhibitor-kinase interactions and propose mechanisms of action.
Main Results:
- Identified limitations of orthosteric inhibitors due to poor selectivity.
- Highlighted the potential of allosteric modulators and peptide-based platforms for enhanced selectivity.
- Provided a comprehensive overview of PKC isoform roles and inhibitor strategies.
Conclusions:
- Next-generation protein kinase modulators require enhanced selectivity, achievable through allosteric binding and novel drug platforms.
- Understanding inhibitor-kinase interactions via molecular modeling is key to designing more effective and safer therapeutics.
- PKC inhibitors hold promise for treating cancer and cardiovascular diseases, warranting further investigation into their selective application.
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