4EZJ

Potent and Selective Inhibitors of PI3K-delta: Obtaining Isoform Selectivity from the Affinity Pocket and Tryptophan Shelf

Summary for 4EZJ

• Entry DOI: 10.2210/pdb4ezj/pdb
• Related: 4EZK 4EZL
• Descriptor: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform, 2-(1-{[2-(5-fluoro-1H-indol-4-yl)-4-(morpholin-4-yl)pyrido[3,2-d]pyrimidin-6-yl]methyl}piperidin-4-yl)propan-2-ol (3 entities in total)
• Functional Keywords: kinase p110, p110-gamma, lipid kinase, cytoplasmic, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P48736
• Total number of polymer chains: 1
• Total formula weight: 111203.62

Authors

Murray, J.M. (deposition date: 2012-05-02, release date: 2013-04-17, Last modification date: 2023-09-13)

Primary citation

Sutherlin, D.P.,Baker, S.,Bisconte, A.,Blaney, P.M.,Brown, A.,Chan, B.K.,Chantry, D.,Castanedo, G.,DePledge, P.,Goldsmith, P.,Goldstein, D.M.,Hancox, T.,Kaur, J.,Knowles, D.,Kondru, R.,Lesnick, J.,Lucas, M.C.,Lewis, C.,Murray, J.,Nadin, A.J.,Nonomiya, J.,Pang, J.,Pegg, N.,Price, S.,Reif, K.,Safina, B.S.,Salphati, L.,Staben, S.,Seward, E.M.,Shuttleworth, S.,Sohal, S.,Sweeney, Z.K.,Ultsch, M.,Waszkowycz, B.,Wei, B.
Potent and selective inhibitors of PI3K-delta: obtaining isoform selectivity from the affinity pocket and tryptophan shelf
Bioorg.Med.Chem.Lett., 22:4296-4302, 2012

PubMed Abstract: A potent inhibitor of PI3Kδ that is ≥ 200 fold selective for the remaining three Class I PI3K isoforms and additional kinases is described. The hypothesis for selectivity is illustrated through structure activity relationships and crystal structures of compounds bound to a K802T mutant of PI3Kγ. Pharmacokinetic data in rats and mice support the use of 3 as a useful tool compound to use for in vivo studies.

PubMed: 22672799
DOI: 10.1016/j.bmcl.2012.05.027

Experimental method

X-RAY DIFFRACTION (2.67 Å)