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

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

  • Bioorg Med Chem Lett. 2018 Jun 1;28(10):1964-1971. doi: 10.1016/j.bmcl.2018.03.032.
Tricia L May-Dracka 1,  Robert Arduini 2,  Andrea Bertolotti-Ciarlet 2,  Govinda Bhisetti 2,  Margot Brickelmaier 3,  Ellen Cahir-McFarland 3,  Istvan Enyedy 2,  Jason D Fontenot 3,  Thomas Hesson 2,  Kevin Little 2,  Joe Lyssikatos 2,  Douglas Marcotte 2,  Timothy McKee 2,  Paramasivam Murugan 2,  Thomas Patterson 2,  Hairuo Peng 2,  Mia Rushe 2,  Laura Silvian 2,  Kerri Spilker 2,  Ping Wu 3,  Zhili Xin 2,  Linda C Burkly 3
Affiliations

Affiliations

  • 1 Biotherapeutic and Medicinal Sciences, Biogen, 225 Binney Street, Cambridge, MA 02142, United States. Electronic address: [email protected].
  • 2 Biotherapeutic and Medicinal Sciences, Biogen, 225 Binney Street, Cambridge, MA 02142, United States.
  • 3 Acute Neurology Research, Biogen, 225 Binney Street, Cambridge, MA 02142, United States.
PMID: 29636220 DOI: 10.1016/j.bmcl.2018.03.032
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.

Keywords

Crystal structure; GLK inhibitor; Germinal center kinase-like kinase; MAP4K3; Protein kinase C-θ; Structure activity relationship.

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