6MUM
Murine PI3K delta kinsae domain - cpd 3
Summary for 6MUM
| Entry DOI | 10.2210/pdb6mum/pdb |
| Descriptor | Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform, [(3S)-3-{[8-(1-ethyl-5-methyl-1H-pyrazol-4-yl)-9-methyl-9H-purin-6-yl]oxy}pyrrolidin-1-yl](oxan-4-yl)methanone (2 entities in total) |
| Functional Keywords | phosphoinositide 3-kinase, isoform-specific inhibitors, transferase, inflammatory disorders |
| Biological source | Mus musculus (Mouse) |
| Total number of polymer chains | 2 |
| Total formula weight | 216526.35 |
| Authors | Fischmann, T.O. (deposition date: 2018-10-23, release date: 2019-05-01, Last modification date: 2023-10-11) |
| Primary citation | Methot, J.L.,Zhou, H.,Kattar, S.D.,McGowan, M.A.,Wilson, K.,Garcia, Y.,Deng, Y.,Altman, M.,Fradera, X.,Lesburg, C.,Fischmann, T.,Li, C.,Alves, S.,Shah, S.,Fernandez, R.,Goldenblatt, P.,Hill, A.,Shaffer, L.,Chen, D.,Tong, V.,McLeod, R.L.,Yu, H.,Bass, A.,Kemper, R.,Gatto, N.T.,LaFranco-Scheuch, L.,Trotter, B.W.,Guzi, T.,Katz, J.D. Structure Overhaul Affords a Potent Purine PI3K delta Inhibitor with Improved Tolerability. J.Med.Chem., 62:4370-4382, 2019 Cited by PubMed Abstract: PI3Kδ catalytic activity is required for immune cell activation, and has been implicated in inflammatory diseases as well as hematological malignancies in which the AKT pathway is overactive. A purine PI3Kδ inhibitor bearing a benzimidazolone-piperidine motif was found to be poorly tolerated in dog, which was attributed to diffuse vascular injury. Several strategies were implemented to mitigate this finding, including reconstruction of the benzimidazolone-piperidine selectivity motif. Structure-based design led to the identification of O- and N-linked heterocycloalkyls, with pyrrolidines being particularly ligand efficient and kinome selective, and having an improved safety pharmacology profile. A representative was advanced into a dog tolerability study where it was found to be well tolerated, with no histopathological evidence of vascular injury. PubMed: 30986068DOI: 10.1021/acs.jmedchem.8b01818 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (3.06 Å) |
Structure validation
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