Protein kinase C inhibitors for immune disorders

Altman, Amnon; Kong, Kok-Fai

doi:10.1016/j.drudis.2014.05.008

Cited by 31 publications

(24 citation statements)

References 43 publications

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“…Hence PKC θ is less likely to result in off‐target immunosuppression . As a result, PKC θ , is highly studied as a potential therapeutic target . The most advanced PKC θ inhibitor to be developed is sotrastaurin (AEB071), which is currently undergoing clinical trials for the treatment of psoriasis and organ transplantation .…”

Section: Therapeutic Potential Of Pkcs In Diseasementioning

confidence: 99%

“…133 As a result, PKCh, is highly studied as a potential therapeutic target. 9 The most advanced PKCh inhibitor to be developed is sotrastaurin (AEB071), which is currently undergoing clinical trials for the treatment of psoriasis and organ transplantation. [134][135][136][137][138] Another promising pharmaceutical PKCh inhibitor is compound 27, for which oral administration in mice led to a decreased IL-2 response.…”

Section: Therapeutic Potential Of Pkcs In Diseasementioning

confidence: 99%

“…In the immune system, PKCs are important mediators of immune cell signalling through the immunological synapse. All PKC isoforms are expressed by immune cells, with the exception of PKC γ which is preferably expressed by the central nervous system . Although ubiquitously expressed, the expression pattern and levels of each PKC isoform are cell‐type specific, highlighting their specific function and non‐redundant roles in the immune system.…”

Section: Introductionmentioning

confidence: 99%

“…All PKC isoforms are expressed by immune cells, with the exception of PKCc which is preferably expressed by the central nervous system. 9 Although ubiquitously expressed, the expression pattern and levels of each PKC isoform are cell-type specific, highlighting their specific function and non-redundant roles in the immune system. Recent data suggest that PKCs have additional, non-traditional roles as nuclear kinases, whereby these enzymes have the capacity to directly regulate gene expression programmes.…”

Section: Introductionmentioning

confidence: 99%

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Protein kinase C in the immune system: from signalling to chromatin regulation

2015

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SummaryProtein kinase C (PKC) form a key family of enzymes involved in signalling pathways that specifically phosphorylates substrates at serine/threonine residues. Phosphorylation by PKC is important in regulating a variety of cellular events such as cell proliferation and the regulation of gene expression. In the immune system, PKCs are involved in regulating signal transduction pathways important for both innate and adaptive immunity, ultimately resulting in the expression of key immune genes. PKCs act as mediators during immune cell signalling through the immunological synapse. PKCs are traditionally known to be cytoplasmic signal transducers and are well embedded in the signalling pathways of cells to mediate the cells' response to a stimulus from the plasma membrane to the nucleus. PKCs are also found to transduce signals within the nucleus, a process that is distinct from the cytoplasmic signalling pathway. There is now growing evidence suggesting that PKC can directly regulate gene expression programmes through a non-traditional role as nuclear kinases. In this review, we will focus on the role of PKCs as key cytoplasmic signal transducers in immune cell signalling, as well as its role in nuclear signal transduction. We will also highlight recent evidence for its newly discovered regulatory role in the nucleus as a chromatin-associated kinase.

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Section: Therapeutic Potential Of Pkcs In Diseasementioning

confidence: 99%

Section: Therapeutic Potential Of Pkcs In Diseasementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Protein kinase C in the immune system: from signalling to chromatin regulation

2015

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“…In consequence of their central role in cellular signaling, PKC and the related classes of DAG-responsive proteins have been found to be prominently involved in cancer [7], diabetes [9], Alzheimer’s disease [10], cardiovascular disease [11] and numerous other conditions [12–14]. Complementary therapeutic strategies have targeted both the catalytic activity and the C1 regulatory domain.…”

Section: Introductionmentioning

confidence: 99%

The C1 domain of Vav3, a novel potential therapeutic target

Kelsey

Géczy

Kaler

et al. 2017

Cellular Signalling

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Vav1/2/3 comprise a protein family with guanyl nucleotide exchange activity for Rho and Rac as well as with motifs conferring adapter activity. Biologically, Vav1 plays a critical role in hematologic cell signaling, whereas Vav2/3 have a wider tissue distribution, but all 3 Vav proteins are implicated in cancer development. A structural feature of Vav1/2/3 is the presence of an atypical C1 domain, which possesses close structural homology to the typical C1 domains of protein kinase C but which fails to bind the second messenger diacylglycerol or the potent analogs, the phorbol esters. Previously, we have shown that five residues in the Vav1 C1 domain are responsible for its lack of phorbol ester binding. Here, we show that the lack of phorbol ester binding of Vav3 has a similar basis. We then explore the consequences of phorbol ester binding to a modified Vav3 in which the C1 domain has been altered to allow phorbol ester binding. We find both disruption of the guanyl nucleotide exchange activity of the modified Vav 3 as well as a shift in localization to the membrane upon phorbol ester treatment. This change in localization is associated with altered interactions with other signaling proteins. The studies provide a first step in assessing the potential for the design of custom C1 domain targeted molecules selective for the atypical C1 domains of Vav family proteins.

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Kinase Inhibitors

Givskov

Nielsen

2017

Methods and Principles in Medicinal Chemistry

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Protein kinase C inhibitors for immune disorders

Cited by 31 publications

References 43 publications

Protein kinase C in the immune system: from signalling to chromatin regulation

Protein kinase C in the immune system: from signalling to chromatin regulation

The C1 domain of Vav3, a novel potential therapeutic target

Kinase Inhibitors

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