Summary for 7OI4
| Entry DOI | 10.2210/pdb7oi4/pdb |
| Descriptor | Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform, N-[5-[2-[(1S)-1-cyclopropylethyl]-7-[[4-[(dimethylamino)methyl]phenyl]sulfamoyl]-1-oxidanylidene-3H-isoindol-5-yl]-4-methyl-1,3-thiazol-2-yl]ethanamide (3 entities in total) |
| Functional Keywords | inhibitor, complex, phosphor inositol 3 kinase, transferase |
| Biological source | Mus musculus (Mouse) |
| Total number of polymer chains | 1 |
| Total formula weight | 125402.25 |
| Authors | Petersen, J. (deposition date: 2021-05-11, release date: 2021-07-14, Last modification date: 2024-05-01) |
| Primary citation | Perry, M.W.D.,Bjorhall, K.,Bold, P.,Brulls, M.,Borjesson, U.,Carlsson, J.,Chang, H.A.,Chen, Y.,Eriksson, A.,Fihn, B.M.,Fransson, R.,Fredlund, L.,Ge, H.,Huang, H.,Karabelas, K.,Lamm Bergstrom, E.,Lever, S.,Lindmark, H.,Mogemark, M.,Nikitidis, A.,Palmgren, A.P.,Pemberton, N.,Petersen, J.,Rodrigo Blomqvist, M.,Smith, R.W.,Thomas, M.J.,Ullah, V.,Tyrchan, C.,Wennberg, T.,Westin Eriksson, A.,Yang, W.,Zhao, S.,Oster, L. Discovery of AZD8154, a Dual PI3K gamma delta Inhibitor for the Treatment of Asthma. J.Med.Chem., 64:8053-8075, 2021 Cited by PubMed Abstract: Starting from our previously described PI3Kγ inhibitors, we describe the exploration of structure-activity relationships that led to the discovery of highly potent dual PI3Kγδ inhibitors. We explored changes in two positions of the molecules, including macrocyclization, but ultimately identified a simpler series with the desired potency profile that had suitable physicochemical properties for inhalation. We were able to demonstrate efficacy in a rat ovalbumin challenge model of allergic asthma and in cells derived from asthmatic patients. The optimized compound, AZD8154, has a long duration of action in the lung and low systemic exposure coupled with high selectivity against off-targets. PubMed: 34080862DOI: 10.1021/acs.jmedchem.1c00434 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.8 Å) |
Structure validation
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