4Q9S

Crystal Structure of human Focal Adhesion Kinase (Fak) bound to Compound1 (3,5-DIHYDRO[1,2,4]TRIAZINO[3,4-C][1,4]BENZOXAZIN-2(1H)-ONE)

Summary for 4Q9S

• Entry DOI: 10.2210/pdb4q9s/pdb
• Related: 4Q9Z
• Descriptor: Focal adhesion kinase 1, 3,5-dihydro[1,2,4]triazino[3,4-c][1,4]benzoxazin-2(1H)-one (3 entities in total)
• Functional Keywords: kinase catalytic domain, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cell junction, focal adhesion: Q05397
• Total number of polymer chains: 1
• Total formula weight: 32323.34

Authors

Argiriadi, M.A.,George, D.M. (deposition date: 2014-05-01, release date: 2014-07-02, Last modification date: 2024-10-16)

Primary citation

George, D.M.,Breinlinger, E.C.,Friedman, M.,Zhang, Y.,Wang, J.,Argiriadi, M.,Bansal-Pakala, P.,Barth, M.,Duignan, D.B.,Honore, P.,Lang, Q.,Mittelstadt, S.,Potin, D.,Rundell, L.,Edmunds, J.J.
Discovery of Selective and Orally Bioavailable Protein Kinase C theta (PKC theta ) Inhibitors from a Fragment Hit.
J.Med.Chem., 58:222-236, 2015

PubMed Abstract: Protein kinase Cθ (PKCθ) regulates a key step in the activation of T cells. On the basis of its mechanism of action, inhibition of this kinase is hypothesized to serve as an effective therapy for autoimmune diseases such as rheumatoid arthritis (RA), inflammatory bowel disease (IBD), and psoriasis. Herein, the discovery of a small molecule PKCθ inhibitor is described, starting from a fragment hit 1 and advancing to compound 41 through the use of structure-based drug design. Compound 41 demonstrates excellent in vitro activity, good oral pharmacokinetics, and efficacy in both an acute in vivo mechanistic model and a chronic in vivo disease model but suffers from tolerability issues upon chronic dosing.

PubMed: 25000588
DOI: 10.1021/jm500669m

Experimental method

X-RAY DIFFRACTION (2.07 Å)