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Cambridge, MA, United States

Roth Flach R.J.,Program in Molecular Medicine | Skoura A.,Cardiovascular and Metabolic Research Unit | Matevossian A.,Program in Molecular Medicine | Danai L.V.,Program in Molecular Medicine | And 16 more authors.
Nature Communications | Year: 2015

Signalling pathways that control endothelial cell (EC) permeability, leukocyte adhesion and inflammation are pivotal for atherosclerosis initiation and progression. Here we demonstrate that the Sterile-20-like mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4), which has been implicated in inflammation, is abundantly expressed in ECs and in atherosclerotic plaques from mice and humans. On the basis of endothelial-specific MAP4K4 gene silencing and gene ablation experiments in Apoe-/-mice, we show that MAP4K4 in ECs markedly promotes Western diet-induced aortic macrophage accumulation and atherosclerotic plaque development. Treatment of Apoe-/-and Ldlr-/-mice with a selective small-molecule MAP4K4 inhibitor also markedly reduces atherosclerotic lesion area. MAP4K4 silencing in cultured ECs attenuates cell surface adhesion molecule expression while reducing nuclear localization and activity of NFκB, which is critical for promoting EC activation and atherosclerosis. Taken together, these results reveal that MAP4K4 is a key signalling node that promotes immune cell recruitment in atherosclerosis.

Bhattacharya S.K.,Worldwide Medicinal Chemistry | Andrews K.,Cardiovascular and Metabolic Research Unit | Beveridge R.,Worldwide Medicinal Chemistry | Cameron K.O.,Worldwide Medicinal Chemistry | And 24 more authors.
ACS Medicinal Chemistry Letters | Year: 2014

The identification of potent, highly selective orally bioavailable ghrelin receptor inverse agonists from a spiro-azetidino-piperidine series is described. Examples from this series have promising in vivo pharmacokinetics and increase glucose-stimulated insulin secretion in human whole and dispersed islets. A physicochemistry-based strategy to increase lipophilic efficiency for ghrelin receptor potency and retain low clearance and satisfactory permeability while reducing off-target pharmacology led to the discovery of 16h. Compound 16h has a superior balance of ghrelin receptor pharmacology and off-target selectivity. On the basis of its promising pharmacological and safety profile, 16h was advanced to human clinical trials. © 2014 American Chemical Society.

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