4EWQ

Human p38 alpha MAPK in complex with a pyridazine based inhibitor

4EWQ の概要

• エントリーDOI: 10.2210/pdb4ewq/pdb
• 分子名称: Mitogen-activated protein kinase 14, 4-[3-(4-FLUOROPHENYL)-1H-PYRAZOL-4-YL]PYRIDINE, 3-phenyl-4-(pyridin-4-yl)-6-[4-(pyrimidin-2-yl)piperazin-1-yl]pyridazine, ... (10 entities in total)
• 機能のキーワード: serine/threonine-protein kinase, structural genomics, center for structural genomics of infectious diseases, csgid, protein kinase domain, transferase, atp binding, phosphorylation, cytosol, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 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: 45502.31

構造登録者

Grum-Tokars, V.,Minasov, G.,Roy, S.,Schavocky, J.,Winsor, J.,Watterson, D.M.,Anderson, W.F.,Center for Structural Genomics of Infectious Diseases (CSGID) (登録日: 2012-04-27, 公開日: 2012-06-27, 最終更新日: 2023-09-13)

主引用文献

Roy, S.M.,Minasov, G.,Arancio, O.,Chico, L.W.,Van Eldik, L.J.,Anderson, W.F.,Pelletier, J.C.,Watterson, D.M.
A Selective and Brain Penetrant p38 alpha MAPK Inhibitor Candidate for Neurologic and Neuropsychiatric Disorders That Attenuates Neuroinflammation and Cognitive Dysfunction.
J.Med.Chem., 62:5298-5311, 2019

PubMed Abstract: The p38αMAPK is a serine/threonine protein kinase and a key node in the intracellular signaling networks that transduce and amplify stress signals into physiological changes. A preponderance of preclinical data and clinical observations established p38αMAPK as a brain drug discovery target involved in neuroinflammatory responses and synaptic dysfunction in multiple degenerative and neuropsychiatric brain disorders. We summarize the discovery of highly selective, brain-penetrant, small molecule p38αMAPK inhibitors that are efficacious in diverse animal models of neurologic disorders. A crystallography and pharmacoinformatic approach to fragment expansion enabled the discovery of an efficacious hit. The addition of secondary pharmacology screens to refinement delivered lead compounds with improved selectivity, appropriate pharmacodynamics, and efficacy. Safety considerations and additional secondary pharmacology screens drove optimization that delivered the drug candidate MW01-18-150SRM (MW150), currently in early stage clinical trials.

PubMed: 30978288
DOI: 10.1021/acs.jmedchem.9b00058

実験手法

X-RAY DIFFRACTION (2.1 Å)