9GCF

HUMAN PI3KDELTA IN COMPLEX WITH ISOCUMARIN INHIBITOR CHF-6523

これはPDB形式変換不可エントリーです。

9GCF の概要

• エントリーDOI: 10.2210/pdb9gcf/pdb
• 分子名称: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform, Phosphatidylinositol 3-kinase regulatory subunit alpha, 3-[(1S)-1-[4-azanyl-3-(5-oxidanylpyridin-3-yl)pyrazolo[3,4-d]pyrimidin-1-yl]ethyl]-4-[3-[(4-methylpiperazin-1-yl)methyl]phenyl]isochromen-1-one (3 entities in total)
• 機能のキーワード: pi3kdelta kinase, pi3kdelta kinase inhibitor, transferase
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 141215.34

構造登録者

Pala, D.,Bruno, P.,Capelli, A.M.,Biagetti, M. (登録日: 2024-08-01, 公開日: 2024-12-18, 最終更新日: 2025-02-26)

主引用文献

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

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: 39635891
DOI: 10.1021/acs.jmedchem.4c02062

実験手法

X-RAY DIFFRACTION (2.89 Å)