5NCY
mPI3Kd IN COMPLEX WITH inh1
Summary for 5NCY
| Entry DOI | 10.2210/pdb5ncy/pdb |
| Descriptor | Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform, 1,2-ETHANEDIOL, SULFATE ION, ... (5 entities in total) |
| Functional Keywords | mi3kd, inhibitor, complex pi3k, transferase |
| Biological source | Mus musculus (Mouse) |
| Cellular location | Cytoplasm : O35904 |
| Total number of polymer chains | 1 |
| Total formula weight | 108364.29 |
| Authors | Petersen, J. (deposition date: 2017-03-06, release date: 2017-06-21, Last modification date: 2024-05-01) |
| Primary citation | Perry, M.W.D.,Bjorhall, K.,Bonn, B.,Carlsson, J.,Chen, Y.,Eriksson, A.,Fredlund, L.,Hao, H.,Holden, N.S.,Karabelas, K.,Lindmark, H.,Liu, F.,Pemberton, N.,Petersen, J.,Rodrigo Blomqvist, S.,Smith, R.W.,Svensson, T.,Terstiege, I.,Tyrchan, C.,Yang, W.,Zhao, S.,Oster, L. Design and Synthesis of Soluble and Cell-Permeable PI3K delta Inhibitors for Long-Acting Inhaled Administration. J. Med. Chem., 60:5057-5071, 2017 Cited by PubMed Abstract: PI3Kδ is a lipid kinase that is believed to be important in the migration and activation of cells of the immune system. Inhibition is hypothesized to provide a powerful yet selective immunomodulatory effect that may be beneficial for the treatment of conditions such as asthma or rheumatoid arthritis. In this work, we describe the identification of inhibitors based on a thiazolopyridone core structure and their subsequent optimization for inhalation. The initially identified compound (13) had good potency and isoform selectivity but was not suitable for inhalation. Addition of basic substituents to a region of the molecule pointing to solvent was tolerated (enzyme inhibition pIC > 9), and by careful manipulation of the pK and lipophilicity, we were able to discover compounds (20b, 20f) with good lung retention and cell potency that could be taken forward to in vivo studies where significant target engagement could be demonstrated. PubMed: 28520415DOI: 10.1021/acs.jmedchem.7b00401 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.9 Å) |
Structure validation
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