7POT

PI3 kinase delta in complex with N-[5-(3,6-dihydro-2H-pyran-4-yl)-2-methoxypyridin-3-yl]benzenesulfonamide

7POT の概要

• エントリーDOI: 10.2210/pdb7pot/pdb
• 分子名称: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform, N-[5-(3,6-dihydro-2H-pyran-4-yl)-2-methoxy-pyridin-3-yl]benzenesulfonamide (3 entities in total)
• 機能のキーワード: pi3 kinase delta, signaling protein
• 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: 108170.07

構造登録者

Rowland, P.,Convery, M. (登録日: 2021-09-09, 公開日: 2021-09-29, 最終更新日: 2024-06-19)

主引用文献

Down, K.,Amour, A.,Anderson, N.A.,Barton, N.,Campos, S.,Cannons, E.P.,Clissold, C.,Convery, M.A.,Coward, J.J.,Doyle, K.,Duempelfeld, B.,Edwards, C.D.,Goldsmith, M.D.,Krause, J.,Mallett, D.N.,McGonagle, G.A.,Patel, V.K.,Rowedder, J.,Rowland, P.,Sharpe, A.,Sriskantharajah, S.,Thomas, D.A.,Thomson, D.W.,Uddin, S.,Hamblin, J.N.,Hessel, E.M.
Discovery of GSK251: A Highly Potent, Highly Selective, Orally Bioavailable Inhibitor of PI3K delta with a Novel Binding Mode.
J.Med.Chem., 64:13780-13792, 2021

PubMed Abstract: Optimization of a previously reported lead series of PI3Kδ inhibitors with a novel binding mode led to the identification of a clinical candidate compound (GSK251). Removal of an embedded Ames-positive heteroaromatic amine by reversing a sulfonamide followed by locating an interaction with Trp760 led to a highly selective compound . Further optimization to avoid glutathione trapping, to enhance potency and selectivity, and to optimize an oral pharmacokinetic profile led to the discovery of compound (GSK215) that had a low predicted daily dose (45 mg, b.i.d) and a rat toxicity profile suitable for further development.

PubMed: 34510892
DOI: 10.1021/acs.jmedchem.1c01102

実験手法

X-RAY DIFFRACTION (2.391 Å)