6DGT

Selective PI3K beta inhibitor bound to PI3K delta

6DGT の概要

• エントリーDOI: 10.2210/pdb6dgt/pdb
• 分子名称: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform, 4-[1-(5,8-difluoroquinolin-4-yl)-2-methyl-4-(4H-1,2,4-triazol-3-yl)-1H-benzimidazol-6-yl]-3-fluoropyridin-2-amine (3 entities in total)
• 機能のキーワード: pi3k delta, p110, inhibitor, transferase-transferase inhibitor complex, transferase/transferase 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: 108110.90

構造登録者

Somoza, J.,Villasenor, A.,McGrath, M. (登録日: 2018-05-18, 公開日: 2018-08-01, 最終更新日: 2024-03-13)

主引用文献

Chandrasekhar, J.,Dick, R.,Van Veldhuizen, J.,Koditek, D.,Lepist, E.I.,McGrath, M.E.,Patel, L.,Phillips, G.,Sedillo, K.,Somoza, J.R.,Therrien, J.,Till, N.A.,Treiberg, J.,Villasenor, A.G.,Zherebina, Y.,Perreault, S.
Atropisomerism by Design: Discovery of a Selective and Stable Phosphoinositide 3-Kinase (PI3K) beta Inhibitor.
J. Med. Chem., 61:6858-6868, 2018

PubMed Abstract: Atropisomerism is a type of axial chirality in which enantiomers or diastereoisomers arise due to hindered rotation around a bond axis. In this manuscript, we report a case in which torsional scan studies guided the thoughtful creation of a restricted axis of rotation between two heteroaromatic systems of a phosphoinositide 3-kinase (PI3K) β inhibitor, generating a pair of atropisomeric compounds with significantly different pharmacological and pharmacokinetic profiles. Emblematic of these differences, the metabolism of inactive ( M)-28 is primarily due to the cytosolic enzyme aldehyde oxidase, while active ( P)-28 has lower affinity for aldehyde oxidase, resulting in substantially better metabolic stability. Additionally, we report torsional scan and experimental studies used to determine the barriers of rotation of this novel PI3Kβ inhibitor.

PubMed: 30015489
DOI: 10.1021/acs.jmedchem.8b00797

実験手法

X-RAY DIFFRACTION (2.601 Å)