8A5X

Crystal structure of phosphatidyl inositol 4-kinase II beta in complex with MM1373

8A5X の概要

• エントリーDOI: 10.2210/pdb8a5x/pdb
• 分子名称: Phosphatidylinositol 4-kinase type 2-beta,Endolysin, 4-azanyl-7-[3-(hydroxymethyl)phenyl]quinazoline-6-carboxamide (3 entities in total)
• 機能のキーワード: lipid, kinase, pi4k2b, inhibitor, transferase
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 59662.21

構造登録者

Klima, M.,Boura, E. (登録日: 2022-06-16, 公開日: 2022-10-05, 最終更新日: 2024-01-31)

主引用文献

Misehe, M.,Klima, M.,Matousova, M.,Chalupska, D.,Dejmek, M.,Sala, M.,Mertlikova-Kaiserova, H.,Boura, E.,Nencka, R.
Structure-based design and modular synthesis of novel PI4K class II inhibitors bearing a 4-aminoquinazoline scaffold.
Bioorg.Med.Chem.Lett., 76:129010-129010, 2022

PubMed Abstract: Novel 4-aminoquinazoline-6-carboxamide derivatives bearing differently substituted aryl or heteroaryl groups at position 7 in the core were rationally designed, synthesized and evaluated for biological activity in vitro as phosphatidylinositol 4-kinase IIα (PI4K2A) inhibitors. The straightforward approach described here enabled the sequential, modular synthesis and broad functionalization of the scaffold in a mere six steps. The SAR investigation reported here is based on detailed structural analysis of the conserved binding mode of ATP and other adenine derivatives to the catalytic site of type II PI4Ks, combined with extensive docking studies. Several compounds exhibited significant activity against PI4K2A. Moreover, we solved a crystal structure of PI4K2B in complex with one of our lead ligand candidates, which validated the ligand binding site and pose predicted by our docking-based ligand model. These discoveries suggest that our structure-based approach may be further developed and employed to synthesize new inhibitors with optimized potency and selectivity for this class of PI4Ks.

PubMed: 36184029
DOI: 10.1016/j.bmcl.2022.129010

実験手法

X-RAY DIFFRACTION (2.4 Å)