9GDI
HUMAN PI3KDELTA IN COMPLEX WITH ISOCUMARIN INHIBITOR 10
This is a non-PDB format compatible entry.
Summary for 9GDI
| Entry DOI | 10.2210/pdb9gdi/pdb |
| Related | 9GCF |
| Descriptor | Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform, Phosphatidylinositol 3-kinase regulatory subunit alpha, 3-[(1S)-1-[4-azanyl-3-(3-fluoranyl-5-oxidanyl-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]ethyl]-4-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)isochromen-1-one, ... (5 entities in total) |
| Functional Keywords | pi3kdelta kinase, pi3kdelta kinase inhibitor, transferase |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 2 |
| Total formula weight | 141174.67 |
| Authors | Pala, D.,Bruno, P.,Capelli, A.M.,Biagetti, M. (deposition date: 2024-08-05, release date: 2024-12-18, Last modification date: 2025-02-26) |
| Primary citation | Bruno, P.,Pala, D.,Micoli, A.,Corsi, M.,Accetta, A.,Carzaniga, L.,Ronchi, P.,Fiorelli, C.,Formica, M.,Pizzirani, D.,Mazzucato, R.,Guariento, S.,Bertolini, S.,Martucci, C.,Allen, A.D.,Mileo, V.,Capacchi, S.,Gallo, P.M.,Fioni, A.,Xanxo Fernandez, S.,Villetti, G.,Puccini, P.,Civelli, M.,Guala, M.,Retini, M.,Martinelli, P.,Visentini, F.,Pavoni, V.,Daldosso, M.,Fontana, S.,Biagetti, M.,Capelli, A.M. Discovery of CHF-6523, an Inhaled Selective PI3K delta Inhibitor for the Treatment of Chronic Obstructive Pulmonary Disease. J.Med.Chem., 68:2444-2465, 2025 Cited by PubMed Abstract: The design of inhaled selective phosphatidylinositol 3-kinase delta (PI3Kδ) inhibitors for the treatment of inflammatory lung diseases was pursued. Knowledge-based design of a novel isocoumarin scaffold that was able to adopt a topology ensured the desired PI3Kδ selectivity. Achievement of low nanomolar cellular potencies through hinge binder group optimization, reduction of intrinsic permeability through head group optimization to extend lung retention, and screening of crystalline forms suitable for administration as dry powders culminated in the identification of compound . This novel inhaled selective PI3Kδ inhibitor displayed durable anti-inflammatory activity in a disease-relevant rat model of Th-2-driven acute lung inflammation and safe and preclinical profiles. Therefore, compound showed the appropriate discovery profile and was progressed to clinical trials in healthy volunteers and chronic obstructive pulmonary disease (COPD) patients as CHF-6523. PubMed: 39635891DOI: 10.1021/acs.jmedchem.4c02062 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.81 Å) |
Structure validation
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