6G6W

HUMAN PI3KDELTA IN COMPLEX WITH LIGAND LASW1976

6G6W の概要

• エントリーDOI: 10.2210/pdb6g6w/pdb
• 分子名称: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform, Phosphatidylinositol 3-kinase regulatory subunit alpha, ~{N}-[3-[4-[[(1~{S})-1-(5-methyl-4-oxidanylidene-3-phenyl-pyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl]amino]-7~{H}-pyrrolo[ 2,3-d]pyrimidin-5-yl]-5-oxidanyl-phenyl]methanesulfonamide, ... (4 entities in total)
• 機能のキーワード: pi3kdelta kinase, proteros biostructures gmbh, 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: 144591.98

構造登録者

Segarra, V.,Hernandez, B.,Jestel, A.,Mortel, M.,Nagel, S. (登録日: 2018-04-03, 公開日: 2018-11-07, 最終更新日: 2024-01-17)

主引用文献

Erra, M.,Taltavull, J.,Bernal, F.J.,Caturla, J.F.,Carrascal, M.,Pages, L.,Mir, M.,Espinosa, S.,Gracia, J.,Dominguez, M.,Sabate, M.,Paris, S.,Maldonado, M.,Hernandez, B.,Bravo, M.,Calama, E.,Miralpeix, M.,Lehner, M.D.,Calbet, M.
Discovery of a Novel Inhaled PI3K delta Inhibitor for the Treatment of Respiratory Diseases.
J. Med. Chem., 61:9551-9567, 2018

PubMed Abstract: Oral PI3Kδ inhibitors such as Idelalisib and Duvelisib have shown efficacy as anticancer agents and Idelalisib has been approved for the treatment of three B-cell cancers. However, Idelalisib has a black box warning on its product label regarding the risks of fatal and serious toxicities including hepatic toxicity, severe diarrhea, colitis, pneumonitis, infections, and intestinal perforation. Some of these side effects are mechanism-related and could hinder the development of Idelalisib for less severe conditions. For respiratory diseases, compounds administered by inhalation are delivered directly to the site of action and may improve the therapeutic index of a drug, minimizing undesired side effects. This work describes the discovery and optimization of inhaled PI3Kδ inhibitors intended for the treatment of severe asthma and COPD. Once the potency was in the desired range, efforts were focused on identifying the particular physicochemical properties that could translate into better lung retention. This medicinal chemistry exercise led to the identification of LAS195319 as a candidate for clinical development.

PubMed: 30351000
DOI: 10.1021/acs.jmedchem.8b00873

実験手法

X-RAY DIFFRACTION (2.72 Å)