4RA5
Human Protein Kinase C THETA IN COMPLEX WITH LIGAND COMPOUND 11a (6-[(1,3-Dimethyl-azetidin-3-yl)-methyl-amino]-4(R)-methyl-7-phenyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one)
Summary for 4RA5
| Entry DOI | 10.2210/pdb4ra5/pdb |
| Related | 4Q9S 4Q9Z 4RA4 |
| Descriptor | HUMAN PROTEIN KINASE C THETA, (1R)-9-[(1,3-dimethylazetidin-3-yl)(methyl)amino]-1-methyl-8-phenyl-3,5-dihydro[1,2,4]triazino[3,4-c][1,4]benzoxazin-2(1H)-one, SODIUM ION, ... (5 entities in total) |
| Functional Keywords | pkc theta kinase, kinase domain, proteros biostructures gmbh, transferase-transferase inhibitor complex, transferase/transferase inhibitor |
| Biological source | Homo sapiens (human) |
| Cellular location | Cytoplasm: Q04759 |
| Total number of polymer chains | 2 |
| Total formula weight | 80151.14 |
| Authors | Argiriadi, M.A.,George, D.M. (deposition date: 2014-09-09, release date: 2014-10-08, Last modification date: 2024-11-06) |
| Primary citation | George, D.M.,Breinlinger, E.C.,Argiriadi, M.A.,Zhang, Y.,Wang, J.,Bansal-Pakala, P.,Duignan, D.B.,Honore, P.,Lang, Q.,Mittelstadt, S.,Rundell, L.,Schwartz, A.,Sun, J.,Edmunds, J.J. Optimized Protein Kinase C theta (PKC theta ) Inhibitors Reveal Only Modest Anti-inflammatory Efficacy in a Rodent Model of Arthritis. J.Med.Chem., 58:333-346, 2015 Cited by PubMed Abstract: We previously demonstrated that selective inhibition of protein kinase Cθ (PKCθ) with triazinone 1 resulted in dose-dependent reduction of paw swelling in a mouse model of arthritis.1,2 However, a high concentration was required for efficacy, thus providing only a minimal safety window. Herein we describe a strategy to deliver safer compounds based on the hypothesis that optimization of potency in concert with good oral pharmacokinetic (PK) properties would enable in vivo efficacy at reduced exposures, resulting in an improved safety window. Ultimately, transformation of 1 yielded analogues that demonstrated excellent potency and PK properties and fully inhibited IL-2 production in an acute model. In spite of good exposure, twice-a-day treatment with 17l in the glucose-6-phosphate isomerase chronic in vivo mouse model of arthritis yielded only moderate efficacy. On the basis of the exposure achieved, we conclude that PKCθ inhibition alone is insufficient for complete efficacy in this rodent arthritis model. PubMed: 25254961DOI: 10.1021/jm5013006 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.61 Å) |
Structure validation
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