4RA4

Crystal Structure of Human Protein Kinase C Alpha in Complex with Compound 28 ((R)-6-((3S,4S)-1,3-Dimethyl-piperidin-4-yl)-7-(2-fluoro-phenyl)-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one)

4RA4 の概要

• エントリーDOI: 10.2210/pdb4ra4/pdb
• 関連するPDBエントリー: 4Q9S 4Q9Z
• 分子名称: Protein kinase C, (1R)-9-[(3S,4S)-1,3-dimethylpiperidin-4-yl]-8-(2-fluorophenyl)-1-methyl-3,5-dihydro[1,2,4]triazino[3,4-c][1,4]benzoxazin-2(1H)-one (3 entities in total)
• 機能のキーワード: kinase domain, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 41269.96

構造登録者

Argiriadi, M.A.,George, D.M. (登録日: 2014-09-09, 公開日: 2014-10-08, 最終更新日: 2024-11-20)

主引用文献

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

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: 25254961
DOI: 10.1021/jm5013006

実験手法

X-RAY DIFFRACTION (2.63 Å)