5ITD

Crystal structure of PI3K alpha with PI3K delta inhibitor

Summary for 5ITD

• Entry DOI: 10.2210/pdb5itd/pdb
• Descriptor: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform, Phosphatidylinositol 3-kinase regulatory subunit alpha, 5-{4-[3-(4-acetylpiperazine-1-carbonyl)phenyl]quinazolin-6-yl}-2-methoxypyridine-3-carbonitrile, ... (4 entities in total)
• Functional Keywords: inhibitor, lipid kinase, pi3k, alpha, delta, transferase-protein transport-inhibitor complex, transferase/protein transport/inhibitor
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 164523.84

Authors

Knapp, M.S.,Elling, R.A. (deposition date: 2016-03-16, release date: 2016-09-07, Last modification date: 2024-04-03)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (3.02 Å)