1. Investigating small molecules to inhibit germinal center kinase-like kinase (GLK/MAP4K3) upstream of PKCθ phosphorylation: Potential therapy to modulate T cell dependent immunity.
- Author
-
May-Dracka TL, Arduini R, Bertolotti-Ciarlet A, Bhisetti G, Brickelmaier M, Cahir-McFarland E, Enyedy I, Fontenot JD, Hesson T, Little K, Lyssikatos J, Marcotte D, McKee T, Murugan P, Patterson T, Peng H, Rushe M, Silvian L, Spilker K, Wu P, Xin Z, and Burkly LC
- Subjects
- Animals, Binding Sites, Cell Line, Humans, Inhibitory Concentration 50, Interleukin-2 metabolism, Mice, Mice, Knockout, Molecular Docking Simulation, Phosphorylation drug effects, Protein Kinase Inhibitors metabolism, Protein Kinase Inhibitors pharmacology, Protein Serine-Threonine Kinases antagonists & inhibitors, Protein Structure, Tertiary, Pyridines chemistry, Pyridines metabolism, Pyridines pharmacology, Structure-Activity Relationship, T-Lymphocytes cytology, T-Lymphocytes drug effects, T-Lymphocytes immunology, Protein Kinase C-theta metabolism, Protein Kinase Inhibitors chemistry, Protein Serine-Threonine Kinases metabolism
- Abstract
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-θ (PKCθ) 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 PKCθ 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., (Copyright © 2018 Elsevier Ltd. All rights reserved.)
- Published
- 2018
- Full Text
- View/download PDF