Protein kinases in cardiovascular diseases

Chen, Jiawen; Li, Yafei; Du, Chong; Wei, Tianwen; Shan, Tiankai; Wang, Liansheng

doi:10.1097/cm9.0000000000001870

Cited by 12 publications

(16 citation statements)

References 114 publications

(243 reference statements)

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“…Nevertheless, the success of kinase inhibitors in cancer treatment has strongly supported their application to the treatment of CVDs as well. Furthermore, kinases that promote cancer are often required for cardiac function, and at least some of these kinase inhibitors have cardiotoxic effects in a significant percentage of patients, suggesting activity in this organ [208][209][210].…”

Section: Pkc In Cardiovascular Diseasesmentioning

confidence: 99%

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

Silnitsky,

Rubin,

Zerihun

et al. 2023

IJMS

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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).

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Section: Pkc In Cardiovascular Diseasesmentioning

confidence: 99%

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

Silnitsky,

Rubin,

Zerihun

et al. 2023

IJMS

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show abstract

“…Protein kinases (a total 518 known in the human kinome) are the key enzymes catalyzing phosphorylation, a posttranslational modification that participates in the regulation of biological processes and molecular functions, such as insulin signal transduction and glucose disposal [23]. PamGene has developed a unique technology to perform real-time measurement of kinase activity.…”

Section: Introductionmentioning

confidence: 99%

Sex-specific sequels of early life stress on serine/threonine kinase activity in visceral adipose tissue from obese mice

Leachman,

Creeden,

Turner

et al. 2024

Preprint

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Adverse childhood experiences (ACEs) are an established independent risk factor for chronic disease development including obesity and hypertension; however, only women exposed to ACEs show a positive relationship with BMI. Our lab has reported that maternal separation and early weaning (MSEW), a mouse model of early life stress, induces sex-specific mechanisms underlying greater blood pressure response to a chronic high fat diet (HF). While female MSEW mice fed a HF display exacerbated perigonadal white adipose tissue (pgWAT) expansion and a metabolic syndrome phenotype compared to controls, male MSEW mice display similar levels of adiposity compared to control counterparts but display neurogenic hypertension. Thus, this study aimed to determine a pgWAT whether there is a sex-specific serine/threonine kinase (STKA) activity associated with early life stress. Frozen pgWAT was collected from MSEW and Control, male and female mice fed a HF to assess STKA activity using the Pamstation12 instrument. Overall, MSEW induces significant reduction of 7 phosphokinases (|Z| >=1.5) in females (QIK, MLK, PKCH, MST, STE7, PEK, FRAY) and 5 in males (AKT, SGK, P38, MARK, CDK), while 15 were downregulated in both sexes (DMPK, PKA, PKG, RSK, PLK, DYRK, NMO, CAMK1, JNK, PAKA, RAD53, ERK, PAKB, PKD, PIM, AMPK). This data provides new insights into the sex-specific dysregulation of the molecular network that regulates cellular phosphorylation signals in visceral adipose tissue and identifies possible target phosphokinases important in adipocyte hypertrophy as a result of exposure to early life stress combined with an unhealthy. Identifying functional metabolic signatures associated with early life stress is critical to elucidate the underlying molecular mechanisms behind the sex-specific obesity risk.

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“…Kinase-mediated phosphorylation is critical for a wide spectrum of cell signaling processes such as transcription, translation, cell proliferation, receptor downregulation, metabolism, and apoptosis 1 . The dysregulation of kinases alters cell function and may lead to diseases such as schizophrenia 2 , Alzheimer's disease 3 , cancer 4 , and cardiovascular diseases 5 . Kinases undergo dynamic conformational changes to elicit their function during cell signaling 6 .…”

Section: Introductionmentioning

confidence: 99%

Allosteric regulation of kinase activity in living cells

Godbole

Dokholyan

2023

Preprint

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The dysregulation of protein kinases is associated with multiple diseases due to the kinases' involvement in a variety of cell signaling pathways. Manipulating protein kinase function, by controlling the active site, is a promising therapeutic and investigative strategy to mitigate and study diseases. Kinase active sites share structural similarities making it difficult to specifically target one kinase, allosteric control allows specific regulation and study of kinase function without directly targeting the active site. Allosteric sites are distal to the active site but coupled via a dynamic network of inter-atomic interactions between residues in the protein. Establishing an allosteric control over a kinase requires understanding the allosteric wiring of the protein. Computational techniques offer effective and inexpensive mapping of the allosteric sites on a protein. Here, we discuss methods to map and regulate allosteric communications in proteins, and strategies to establish control over kinase functions in live cells and organisms. Protein molecules, or "sensors" are engineered to function as tools to control allosteric activity of the protein as these sensors have high spatiotemporal resolution and help in understanding cell phenotypes after immediate activation or inactivation of a kinase. Traditional methods used to study protein functions, such as knockout, knockdown, or mutation, cannot offer a sufficiently high spatiotemporal resolution. We discuss the modern repertoire of tools to regulate protein kinases as we enter a new era in deciphering cellular signaling and developing novel approaches to treat diseases associated with signal dysregulation.

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Protein kinases in cardiovascular diseases

Cited by 12 publications

References 114 publications

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

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

Sex-specific sequels of early life stress on serine/threonine kinase activity in visceral adipose tissue from obese mice

Allosteric regulation of kinase activity in living cells

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