9D75

Human p38alpha MAP Kinase in complex with 1-(Cyclohexylmethyl)-1H-indazole derivative; OSF346

これはPDB形式変換不可エントリーです。

9D75 の概要

• エントリーDOI: 10.2210/pdb9d75/pdb
• 分子名称: Mitogen-activated protein kinase 14, 1-(cyclohexylmethyl)-5-[(2,4-difluorophenyl)methyl]-N-[2-(dimethylamino)ethyl]-1H-indazole-6-carboxamide, 4-[3-(4-FLUOROPHENYL)-1H-PYRAZOL-4-YL]PYRIDINE, ... (4 entities in total)
• 機能のキーワード: p38, kinase, inhibitor, complex, transferase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 40441.34

構造登録者

Brunzelle, J.S.,Shuvalova, L.,Benetik, S.F.,Roy, S.M.,Watterson, D.M.,Gobec, S. (登録日: 2024-08-16, 公開日: 2025-09-24)

主引用文献

Ferjancic Benetik, S.,Proj, M.,Knez, D.,Kosak, U.,Meden, A.,Krajsek, K.,Pislar, A.,Horvat, S.,Svajger, U.,Tesic, N.,Pulkrabkova, L.,Soukup, O.,Skarka, A.,Andrys, R.,Brazzolotto, X.,Igert, A.,Nachon, F.,Dias, J.,Detka, J.,Gdula-Argasinska, J.,Wyska, E.,Szafarz, M.,Manik, A.,Plachtij, N.,Musilek, K.,Salat, K.,Obreza, A.,Gobec, S.
Targeting Neuroinflammation and Cognitive Decline: First-in-Class Dual Butyrylcholinesterase and p38 alpha Mitogen-Activated Protein Kinase Inhibitors.
J.Med.Chem., 68:17378-17411, 2025

PubMed Abstract: The currently approved drugs for the treatment of Alzheimer's disease (AD) fail to address its interconnected pathological processes. Inhibition of butyrylcholinesterase (BChE) and p38α mitogen-activated protein kinase (p38α MAPK) offers an innovative dual approach to mitigate two major drivers of neurodegeneration in AD: cholinergic deficit and neuroinflammation. Using structure-based drug design and a library of known p38α MAPK inhibitors, we developed first-in-class, selective dual BChE/p38α MAPK inhibitors with balanced activity against both targets. The X-ray crystal structures of the two most promising molecules bound to both enzymes were solved. Those ligands effectively reduced the production of proinflammatory markers in vitro and ex vivo in phytohemagglutinin/lipopolysaccharide neuroinflammation models. Remarkably, these compounds also significantly improved cognition in scopolamine- and lipopolysaccharide-induced models of cognitive dysfunction in mice. Because our dual-acting inhibitors target both the symptoms and the underlying neuropathology, they offer an innovative and comprehensive strategy to combat AD.

PubMed: 40779804
DOI: 10.1021/acs.jmedchem.5c00933

実験手法

X-RAY DIFFRACTION (2.13 Å)