PI3Kδ and PI3Kγ as Targets for Autoimmune and Inflammatory Diseases

Cushing, Timothy D.; Metz, Daniela; Whittington, Douglas A.; McGee, Lawrence R.

doi:10.1021/jm300847w

Cited by 78 publications

(81 citation statements)

References 98 publications

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“…For example, 16 compared very favorably to 17, with the B cell proliferation cellular activity improved over 11-fold and the HWB intrinsic unbound potency increased by a factor of 5. The intrinsic rat iv clearance for these analogs 12,14,15,16, and 17 remained high despite the α-methyl group's contribution to improvements in other properties such as potency.…”

Section: ■ Introductionmentioning

confidence: 99%

Discovery and in Vivo Evaluation of (S)-N-(1-(7-Fluoro-2-(pyridin-2-yl)quinolin-3-yl)ethyl)-9H-purin-6-amine (AMG319) and Related PI3Kδ Inhibitors for Inflammation and Autoimmune Disease

Cushing

Hao²,

Shin³

et al. 2014

J. Med. Chem.

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The development and optimization of a series of quinolinylpurines as potent and selective PI3Kδ kinase inhibitors with excellent physicochemical properties are described. This medicinal chemistry effort led to the identification of 1 (AMG319), a compound with an IC50 of 16 nM in a human whole blood assay (HWB), excellent selectivity over a large panel of protein kinases, and a high level of in vivo efficacy as measured by two rodent disease models of inflammation.

show abstract

Section: ■ Introductionmentioning

confidence: 99%

Discovery and in Vivo Evaluation of (S)-N-(1-(7-Fluoro-2-(pyridin-2-yl)quinolin-3-yl)ethyl)-9H-purin-6-amine (AMG319) and Related PI3Kδ Inhibitors for Inflammation and Autoimmune Disease

Cushing

Hao²,

Shin³

et al. 2014

J. Med. Chem.

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“…PI3K is a key signaling molecule that controls numerous cellular functions (29). In the liver, PI3K activation promotes cytokine production and subsequent hepatocyte proliferation following partial hepatectomy (30).…”

Section: Discussionmentioning

confidence: 99%

NF-κB inhibition alleviates carbon tetrachloride-induced liver fibrosis via suppression of activated hepatic stellate cells

Wang

Liu

et al. 2014

Experimental and Therapeutic Medicine

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An effective treatment for hepatic fibrosis is not available clinically. Nuclear factor (NF)-κB plays a central role in inflammation and fibrosis. The aim of the present study was to investigate the effect of an NF-κB inhibitor, BAY-11–7082 (BAY), on mouse liver fibrosis. The effects of BAY on hepatic stellate cell (HSC) activation were measured in the lipopolysaccharide-activated rat HSC-T6 cell line. In addition, the therapeutic effect of BAY was studied in vivo using a model of hepatic fibrosis induced by carbon tetrachloride (CCl4) in mice. BAY effectively decreased the cell viability of activated HSC-T6 cells and suppressed HSC-T6 activation by downregulating the expression of collagen I and α-smooth muscle actin. BAY significantly inhibited the phosphorylation of phosphatidylinositol 3-kinase (PI3K) and serine/threonine kinase-protein kinase B (Akt) in activated HSC-T6 cells. In addition, administration of BAY attenuated mouse liver fibrosis induced by CCl4, as shown by histology and the expression of profibrogenic markers. BAY also significantly decreased the levels of serum alanine aminotransferase in this model of hepatic fibrosis. Therefore, the results of the present study demonstrate that BAY attenuates liver fibrosis by blocking PI3K and Akt phosphorylation in activated HSCs. Thus, BAY demonstrates therapeutic potential as a treatment for hepatic fibrosis.

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“…The goal of this work is to inhibit only the activity of the relevant p110 catalytic subunit contributing to the pathogenesis of a disease, while sparing the activity of the other catalytic subunits, thus reducing the risk for off-target and potentially toxic side effects. The Class IA PI3K catalytic subunit, p110d, like the sole Class IB PI3K catalytic subunit, p110c, is expressed predominantly in hematopoietic cells, in contrast to p110a and p110b, which are ubiquitously expressed, suggesting that p110d and p110c might be ideal pharmacologic targets in diseases involving the hematopoietic system such as allergic disorders, autoimmune disorders, and leukemias [28][29][30]. While p110c is associated with signaling mediated by G-Protein-Coupled Receptors (GPCRs), p110d is typically found promoting activation of PI3K signaling downstream of receptor tyrosine kinases and cytokine receptors, indicating that p110d and p110c bear unique functions, though much work has recently demonstrated their potential cooperation in many diseases processes [30].…”

Section: The Catalytic Subunit P110d As a Potential Target In Hematolmentioning

confidence: 99%

Phospho-Inositol-3-Kinase Activity and Dysregulation in Pediatric Leukemia and Lymphoma

Goodwin

Chan

2016

Cancer Drug Discovery and Development

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PI3Kδ and PI3Kγ as Targets for Autoimmune and Inflammatory Diseases

Cited by 78 publications

References 98 publications

Discovery and in Vivo Evaluation of (S)-N-(1-(7-Fluoro-2-(pyridin-2-yl)quinolin-3-yl)ethyl)-9H-purin-6-amine (AMG319) and Related PI3Kδ Inhibitors for Inflammation and Autoimmune Disease

Discovery and in Vivo Evaluation of (S)-N-(1-(7-Fluoro-2-(pyridin-2-yl)quinolin-3-yl)ethyl)-9H-purin-6-amine (AMG319) and Related PI3Kδ Inhibitors for Inflammation and Autoimmune Disease

NF-κB inhibition alleviates carbon tetrachloride-induced liver fibrosis via suppression of activated hepatic stellate cells

Phospho-Inositol-3-Kinase Activity and Dysregulation in Pediatric Leukemia and Lymphoma

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