5AE8

Crystal structure of mouse PI3 kinase delta in complex with GSK2269557

Summary for 5AE8

• Entry DOI: 10.2210/pdb5ae8/pdb
• Related: 5AE9
• Descriptor: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform, 6-(1H-Indol-4-yl)-4-(5-{[4-(1-methylethyl)-1-piperazinyl]methyl}-1,3-oxazol-2-yl)-1H-indazole (3 entities in total)
• Functional Keywords: transferase, pi3 kinase delta
• Biological source: Mus musculus (Mouse)
• Total number of polymer chains: 1
• Total formula weight: 108264.20

Authors

Down, K.D.,Amour, A.,Baldwin, I.R.,Cooper, A.W.J.,Deakin, A.M.,Felton, L.M.,Guntrip, S.B.,Hardy, C.,Harrison, Z.A.,Jones, K.L.,Jones, P.,Keeling, S.E.,Le, J.,Livia, S.,Lucas, F.,Lunniss, C.J.,Parr, N.J.,Robinson, E.,Rowland, P.,Smith, S.,Thomas, D.A.,Vitulli, G.,Washio, Y.,Hamblin, N. (deposition date: 2015-08-26, release date: 2015-09-16, Last modification date: 2024-06-19)

Primary citation

Down, K.,Amour, A.,Baldwin, I.R.,Cooper, A.W.J.,Deakin, A.M.,Felton, L.M.,Guntrip, S.B.,Hardy, C.,Harrison, Z.A.,Jones, K.L.,Jones, P.,Keeling, S.E.,Le, J.,Livia, S.,Lucas, F.,Lunniss, C.J.,Parr, N.J.,Robinson, E.,Rowland, P.,Smith, S.,Thomas, D.A.,Vitulli, G.,Washio, Y.,Hamblin, J.N.
Optimization of Novel Indazoles as Highly Potent and Selective Inhibitors of Phosphoinositide 3-Kinase Gamma for the Treatment of Respiratory Disease.
J.Med.Chem., 58:7381-, 2015

PubMed Abstract: Optimization of lead compound 1, through extensive use of structure-based design and a focus on PI3Kδ potency, isoform selectivity, and inhaled PK properties, led to the discovery of clinical candidates 2 (GSK2269557) and 3 (GSK2292767) for the treatment of respiratory indications via inhalation. Compounds 2 and 3 are both highly selective for PI3Kδ over the closely related isoforms and are active in a disease relevant brown Norway rat acute OVA model of Th2-driven lung inflammation.

PubMed: 26301626
DOI: 10.1021/ACS.JMEDCHEM.5B00767

Experimental method

X-RAY DIFFRACTION (2.42 Å)