5IS5

Discovery and Pharmacological Characterization of Novel Quinazoline-based PI3K delta-selective Inhibitors

5IS5 の概要

• エントリーDOI: 10.2210/pdb5is5/pdb
• 分子名称: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform, 5-{4-[3-(4-acetylpiperazine-1-carbonyl)phenyl]quinazolin-6-yl}-2-methoxypyridine-3-carbonitrile (3 entities in total)
• 機能のキーワード: phosphoinositide 3-kinase, isoform-sepcific inhibitors, transferase
• 由来する生物種: Mus musculus (Mouse)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 120491.99

構造登録者

Gutmann, S.,Rummel, G.,Shrestha, B. (登録日: 2016-03-15, 公開日: 2016-08-10, 最終更新日: 2024-01-10)

主引用文献

Hoegenauer, K.,Soldermann, N.,Stauffer, F.,Furet, P.,Graveleau, N.,Smith, A.B.,Hebach, C.,Hollingworth, G.J.,Lewis, I.,Gutmann, S.,Rummel, G.,Knapp, M.,Wolf, R.M.,Blanz, J.,Feifel, R.,Burkhart, C.,Zecri, F.
Discovery and Pharmacological Characterization of Novel Quinazoline-Based PI3K Delta-Selective Inhibitors.
Acs Med.Chem.Lett., 7:762-767, 2016

PubMed Abstract: Inhibition of the lipid kinase PI3Kδ is a promising principle to treat B and T cell driven inflammatory diseases. Using a scaffold deconstruction-reconstruction strategy, we identified 4-aryl quinazolines that were optimized into potent PI3Kδ isoform selective analogues with good pharmacokinetic properties. With compound 11, we illustrate that biochemical PI3Kδ inhibition translates into modulation of isoform-dependent immune cell function (human, rat, and mouse). After oral administration of compound 11 to rats, proximal PD markers are inhibited, and dose-dependent efficacy in a mechanistic plaque forming cell assay could be demonstrated.

PubMed: 27563400
DOI: 10.1021/acsmedchemlett.6b00119

実験手法

X-RAY DIFFRACTION (2.85 Å)