5O83

Discovery of CDZ173 (leniolisib), Representing a Structurally Novel Class of PI3K Delta-Selective Inhibitors

5O83 の概要

• エントリーDOI: 10.2210/pdb5o83/pdb
• 分子名称: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform, Leniolisib (3 entities in total)
• 機能のキーワード: kinase, transferase, pi3k delta, inhibitor
• 由来する生物種: Mus musculus (Mouse)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 108402.25

構造登録者

Gutmann, S.,Rummel, G.,Shrestha, B. (登録日: 2017-06-12, 公開日: 2017-09-20, 最終更新日: 2024-05-08)

主引用文献

Hoegenauer, K.,Soldermann, N.,Zecri, F.,Strang, R.S.,Graveleau, N.,Wolf, R.M.,Cooke, N.G.,Smith, A.B.,Hollingworth, G.J.,Blanz, J.,Gutmann, S.,Rummel, G.,Littlewood-Evans, A.,Burkhart, C.
Discovery of CDZ173 (Leniolisib), Representing a Structurally Novel Class of PI3K Delta-Selective Inhibitors.
ACS Med Chem Lett, 8:975-980, 2017

PubMed Abstract: The predominant expression of phosphoinositide 3-kinase δ (PI3Kδ) in leukocytes and its critical role in B and T cell functions led to the hypothesis that selective inhibitors of this isoform would have potential as therapeutics for the treatment of allergic and inflammatory disease. Targeting specifically PI3Kδ should avoid potential side effects associated with the ubiquitously expressed PI3Kα and β isoforms. We disclose how morphing the heterocyclic core of previously discovered 4,6-diaryl quinazolines to a significantly less lipophilic 5,6,7,8-tetrahydropyrido[4,3-]pyrimidine, followed by replacement of one of the phenyl groups with a pyrrolidine-3-amine, led to a compound series with an optimal on-target profile and good ADME properties. A final lipophilicity adjustment led to the discovery of CDZ173 (leniolisib), a potent PI3Kδ selective inhibitor with suitable properties and efficacy for clinical development as an anti-inflammatory therapeutic. , CDZ173 inhibits a large spectrum of immune cell functions, as demonstrated in B and T cells, neutrophils, monocytes, basophils, plasmocytoid dendritic cells, and mast cells. , CDZ173 inhibits B cell activation in rats and monkeys in a concentration- and time-dependent manner. After prophylactic or therapeutic dosing, CDZ173 potently inhibited antigen-specific antibody production and reduced disease symptoms in a rat collagen-induced arthritis model. Structurally, CDZ173 differs significantly from the first generation of PI3Kδ and PI3Kγδ-selective clinical compounds. Therefore, CDZ173 could differentiate by a more favorable safety profile. CDZ173 is currently in clinical studies in patients suffering from primary Sjögren's syndrome and in APDS/PASLI, a disease caused by gain-of-function mutations of PI3Kδ.

PubMed: 28947947
DOI: 10.1021/acsmedchemlett.7b00293

実験手法

X-RAY DIFFRACTION (2.9 Å)