TY - JOUR
T1 - An Update on Protein Kinases as Therapeutic Targets—Part I
T2 - Protein Kinase C Activation and Its Role in Cancer and Cardiovascular Diseases
AU - Silnitsky, Shmuel
AU - Rubin, Samuel J.S.
AU - Zerihun, Mulate
AU - Qvit, Nir
N1 - Publisher Copyright:
© 2023 by the authors.
PY - 2023/12/18
Y1 - 2023/12/18
N2 - 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).
AB - 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).
KW - allosteric
KW - cancer
KW - cardiovascular disease
KW - peptides
KW - protein kinase
KW - protein kinase C (PKC)
UR - http://www.scopus.com/inward/record.url?scp=85180724143&partnerID=8YFLogxK
U2 - 10.3390/ijms242417600
DO - 10.3390/ijms242417600
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C2 - 38139428
AN - SCOPUS:85180724143
SN - 1661-6596
VL - 24
JO - International Journal of Molecular Sciences
JF - International Journal of Molecular Sciences
IS - 24
M1 - 17600
ER -