Investigating small molecules to inhibit germinal center kinase-like kinase (GLK/MAP4K3) upstream of PKCθ phosphorylation: Potential therapy to modulate T cell dependent immunity

被引：2

作者：

May-Dracka, Tricia L. ^{[1
]}

Arduini, Robert ^{[1
]}

Bertolotti-Ciarlet, Andrea ^{[1
]}

Bhisetti, Govinda ^{[1
]}

Brickelmaier, Margot ^{[2
]}

Cahir-McFarland, Ellen ^{[2
]}

Enyedy, Istvan ^{[1
]}

Fontenot, Jason D. ^{[2
]}

Hesson, Thomas ^{[1
]}

Little, Kevin ^{[1
]}

Lyssikatos, Joe ^{[1
]}

Marcotte, Douglas ^{[1
]}

McKee, Timothy ^{[1
]}

Murugan, Paramasivam ^{[1
]}

Patterson, Thomas ^{[1
]}

Peng, Hairuo ^{[1
]}

Rushe, Mia ^{[1
]}

Silvian, Laura ^{[1
]}

Spilker, Kerri ^{[1
]}

Wu, Ping ^{[2
]}

Xin, Zhili ^{[1
]}

Burkly, Linda C. ^{[2
]}

机构：

[1] Biogen Inc, Biotherapeut & Med Sci, 225 Binney St, Cambridge, MA 02142 USA

[2] Biogen Inc, Acute Neurol Res, 225 Binney St, Cambridge, MA 02142 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2018年 / 28卷 / 10期

关键词：

Germinal center kinase-like kinase; MAP4K3; GLK inhibitor; Structure activity relationship; Crystal structure; Protein kinase C-theta; ACTIVATION; OPTIMIZATION;

D O I：

10.1016/j.bmcl.2018.03.032

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Germinal center kinase-like kinase (GLK, also known as MAP4K3) has been hypothesized to have an effect on key cellular activities, including inflammatory responses. GLK is required for activation of protein kinase C-0 (PKC theta) in T cells. Controlling the activity of T helper cell responses could be valuable for the treatment of autoimmune diseases. This approach circumvents previous unsuccessful approaches to target PKC theta directly. The use of structure based drug design, aided by the first crystal structure of GLK, led to the discovery of several inhibitors that demonstrate potent inhibition of GLK biochemically and in relevant cell lines. (C) 2018 Elsevier Ltd. All rights reserved.

引用

页码：1964 / 1971

页数：8

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