Progress in the Development of Small Molecule Therapeutics Targeting Th17 Cell Function for the Treatment of Immune-Inflammatory Diseases

Shuttleworth, Stephen J.; Townsend, Paul A.; Silva, Franck; Cecil, Alexander; Hill, Thomas; Tomassi, Cyrille; Rogers, Helen; Harrison, Rebecca

doi:10.1016/b978-0-12-381290-2.00003-3

Cited by 9 publications

(12 citation statements)

References 125 publications

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“…By contrast, the p110δ subtype, which has also been shown to play a central function in the recruitment and activation of a range of immune and inflammatory cells [ 22 - 24 ], has become a hotly pursued target in small molecule drug discovery circles. Co-crystal structures of this isoform were recently resolved [ 25 ], and there are several p110δ-targeted inhibitors that are currently in preclinical development – with two having now entered early phase clinical studies – for the treatment of haematological cancer and immune-inflammatory disorders [ 4 , 26 ].…”

Section: Class I Pi3k Isoforms and Mtor In Chronic Disease: Potentialmentioning

confidence: 99%

Progress in the Preclinical Discovery and Clinical Development of Class I and Dual Class I/IV Phosphoinositide 3-Kinase (PI3K) Inhibitors

Shuttleworth

Silva²,

Cecil³

et al. 2011

CMC

100

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The phosphoinositide 3-kinases (PI3Ks) constitute an important family of lipid kinase enzymes that control a range of cellular processes through their regulation of a network of signal transduction pathways, and have emerged as important therapeutic targets in the context of cancer, inflammation and cardiovascular diseases. Since the mid-late 1990s, considerable progress has been made in the discovery and development of small molecule ATP-competitive PI3K inhibitors, a number of which have entered early phase human trials over recent years from which key clinical results are now being disclosed. This review summarizes progress made to date, primarily on the discovery and characterization of class I and dual class I/IV subtype inhibitors, together with advances that have been made in translational and clinical research, notably in cancer.

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Section: Class I Pi3k Isoforms and Mtor In Chronic Disease: Potentialmentioning

confidence: 99%

Progress in the Preclinical Discovery and Clinical Development of Class I and Dual Class I/IV Phosphoinositide 3-Kinase (PI3K) Inhibitors

Shuttleworth

Silva²,

Cecil³

et al. 2011

CMC

100

View full text Add to dashboard Cite

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“…[1][2][3][4] The T-helper cell 17 (Th17) lineage is a subset of effector memory T cells that plays a critical role in the induction of tissue inflammation and tissue destruction that are hallmarks of many immune-inflammatory diseases. 5 Th17 cells are characterized by their CD4 þ status and can secrete a specific cluster of cytokines, notably the interleukins IL-17, IL-22, and IL-23. IL-17 has an essential function in the development of autoimmunity and allergic reactions.…”

mentioning

confidence: 99%

“…IL-17 has an essential function in the development of autoimmunity and allergic reactions. 5 To our knowledge, there is only 1 study in the literature that investigates the relationship between IL-17 and SSPE. The authors report that the specific polymorphism of the IL-17 gene is one of the factors determining susceptibility to SSPE.…”

mentioning

confidence: 99%

“…6 IL-22 possesses proinflammatory properties, and IL-23 is a critical cytokine involved in autoimmune inflammation of the brain. 5 Most SSPE patients have defects in measles virus-specific production of IFN-g, which is produced by Th1-type cells. 7 IL-12 promotes the development of Th1 responses and is a powerful inducer of IFN-g production.…”

mentioning

confidence: 99%

“…6 IL-22 possesses proinflammatory properties, and IL-23 is a critical cytokine involved in autoimmune inflammation of the brain. 5…”

mentioning

confidence: 99%

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Role of the Th1 and Th17 Pathway in Subacute Sclerosing Panencephalitis

Uygun

Burgucu

et al. 2019

J Child Neurol

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Subacute sclerosing panencephalitis (SSPE) is a progressive and fatal disease caused by reactivation of a mutated measles virus in brain tissue. The process of reactivation is yet to be elucidated. In this study, the possible roles of the Th1 (interleukin [IL]-12, interferon [IFN]-γ) and the Th17 axis (IL-23, IL-17, IL-22), particularly of IL-17, in the pathogenesis of SSPE were investigated. Briefly, mononuclear cells from SSPE patients were stimulated using measles virus peptide, and the release of IL-12, IL-23, IL-22, IFN-γ, and IL-17 cytokines was measured using enzyme-linked immunosorbent assay and/or enzyme-linked immunosorbent spot assay (ELISpot). We found that in comparison to the mononuclear cells obtained from healthy donors, cells from SSPE patients exhibited increased levels of IL-12, IL-23, IL-17, IL-22, and IFN-γ cytokines in response to measles virus stimulation. However, the same result was not obtained with cytomegalovirus and phytohemagglutinin. Using flow cytometry, mononuclear cells obtained from SSPE patients and healthy controls were also analyzed for the presence of intracellular IL-17 in response to measles virus stimulation. On stimulation, the number of IL-17-positive cells were found to be higher among mononuclear cells obtained from the patients. In addition, the numbers of IL-17- and IFN-γ-positive cells were significantly increased in SSPE patients. In conclusion, this study demonstrates that both the IL-12/IFN-γ and the IL-23/IL-17/IL-22 pathways are functionally abnormal in SSPE pathogenesis. Targeting these pathways and their specific pro-inflammatory mediator production may provide a new strategy to suppress SSPE development.

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CRISPR/Cas9 guided genome and epigenome engineering and its therapeutic applications in immune mediated diseases

Singh

Hawkins

Lahesmaa

et al. 2019

Seminars in Cell & Developmental Biology

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Progress in the Development of Small Molecule Therapeutics Targeting Th17 Cell Function for the Treatment of Immune-Inflammatory Diseases

Cited by 9 publications

References 125 publications

Progress in the Preclinical Discovery and Clinical Development of Class I and Dual Class I/IV Phosphoinositide 3-Kinase (PI3K) Inhibitors

Progress in the Preclinical Discovery and Clinical Development of Class I and Dual Class I/IV Phosphoinositide 3-Kinase (PI3K) Inhibitors

Role of the Th1 and Th17 Pathway in Subacute Sclerosing Panencephalitis

CRISPR/Cas9 guided genome and epigenome engineering and its therapeutic applications in immune mediated diseases

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