6ZAA

PI3K Delta in complex with methoxy(methylsulfamoyl)pyridinylN(methylpiperidinyl)dihydrobenzoxazinecarboxamide

6ZAA の概要

• エントリーDOI: 10.2210/pdb6zaa/pdb
• 分子名称: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform, 4-[6-methoxy-5-(methylsulfamoyl)pyridin-3-yl]-~{N}-(1-methylpiperidin-4-yl)-2,3-dihydro-1,4-benzoxazine-6-carboxamide (3 entities in total)
• 機能のキーワード: macrocycle, pi3k delta, thermodynamics, transferase
• 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: 108299.23

構造登録者

Convery, M.A.,Hardy, C.J.,Spencer, J.A.,Rowland, P. (登録日: 2020-06-05, 公開日: 2020-07-15, 最終更新日: 2024-06-19)

主引用文献

Spencer, J.A.,Baldwin, I.R.,Barton, N.,Chung, C.W.,Convery, M.A.,Edwards, C.D.,Jamieson, C.,Mallett, D.N.,Rowedder, J.E.,Rowland, P.,Thomas, D.A.,Hardy, C.J.
Design and Development of a Macrocyclic Series Targeting Phosphoinositide 3-Kinase delta.
Acs Med.Chem.Lett., 11:1386-1391, 2020

PubMed Abstract: A macrocyclization approach has been explored on a series of benzoxazine phosphoinositide 3-kinase δ inhibitors, resulting in compounds with improved potency, permeability, and clearance while maintaining good solubility. The thermodynamics of binding was explored via surface plasmon resonance, and the binding of lead macrocycle was found to be almost exclusively entropically driven compared with progenitor , which demonstrated both enthalpic and entropic contributions. The pharmacokinetics of macrocycle was also explored , where it showed reduced clearance when compared with the progenitor . This work adds to the growing body of evidence that macrocyclization could provide an alternative and complementary approach to the design of small-molecule inhibitors, with the potential to deliver differentiated properties.

PubMed: 32676144
DOI: 10.1021/acsmedchemlett.0c00061

実験手法

X-RAY DIFFRACTION (2.52 Å)