ArticleJournal of immunology (Baltimore, Md. : 1950)2017
Novel Noncatalytic Substrate-Selective p38α-Specific MAPK Inhibitors with Endothelial-Stabilizing and Anti-Inflammatory Activity.
Article in Journal of immunology (Baltimore, Md. : 1950), 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 39 citations in OpenAlex.
- Mapping of dynamic allostery within p38 alpha kinase via network analyses and NMR spectroscopy.Nature communications · 2026Article
- Targeting druggable kinases in neuropathic pain.npj drug discovery · 2026Review
- Identification and validation of the VEGF/p38MAPK/HSP27 pro-tumor inflammatory pathway: screening of active components fromFrontiers in immunology · 2025Article
- Mechanism of Yixishu lotion in the treatment of vaginitis based on network pharmacology combined with experimental validation: an experimental research study.Annals of medicine and surgery (2012) · 2023Article
- Pulmonary inflammation and fibroblast immunoregulation: from bench to bedside.The Journal of clinical investigation · 2023Review
- Comparison of Quantitative Mass Spectrometric Methods for Drug Target Identification by Thermal Proteome Profiling.Journal of proteome research · 2023Article
- Characterization of p38α autophosphorylation inhibitors that target the non-canonical activation pathway.Nature communications · 2023Article
- Novel small-molecule compound VCP979 attenuates renal fibrosis in male rats with unilateral ureteral obstruction.Experimental biology and medicine (Maywood, N.J.) · 2023Article
- Substrate-selective small-molecule modulators of enzymes: Mechanisms and opportunities.Current opinion in chemical biology · 2023Review
- Alleviation of acute pancreatitis-associated lung injury by inhibiting the p38 mitogen-activated protein kinase pathway in pulmonary microvascular endothelial cells.World journal of gastroenterology · 2021Article
- Diversity and versatility of p38 kinase signalling in health and disease.Nature reviews. Molecular cell biology · 2021Review
- Atypical p38 Signaling, Activation, and Implications for Disease.International journal of molecular sciences · 2021Review
- Mechanistic Analysis of an Extracellular Signal-Regulated Kinase 2-Interacting Compound that Inhibits Mutant BRAF-Expressing Melanoma Cells by Inducing Oxidative Stress.The Journal of pharmacology and experimental therapeutics · 2021Article
- Kinase inhibitors in the treatment of obstructive pulmonary diseases.Current opinion in pharmacology · 2020Review
- A temperature-dependent conformational shift in p38α MAPK substrate-binding region associated with changes in substrate phosphorylation profile.The Journal of biological chemistry · 2019Article
- Review
Corrections and comments
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Authors and funding
12 authors at 1 institution in 1 country.
Funding
Abstract
The p38 MAPK family is composed of four kinases of which p38α/MAPK14 is the major proinflammatory member. These kinases contribute to many inflammatory diseases, but the currently available p38 catalytic inhibitors (e.g., SB203580) are poorly effective and cause toxicity. We reasoned that the failure of catalytic p38 inhibitors may derive from their activity against noninflammatory p38 isoforms (e.g., p38β/MAPK11) and loss of all p38α-dependent responses, including anti-inflammatory, counterregulatory responses via mitogen- and stress-activated kinase (MSK) 1/2 and Smad3. We used computer-aided drug design to target small molecules to a pocket near the p38α glutamate-aspartate (ED) substrate-docking site rather than the catalytic site, the sequence of which had only modest homology among p38 isoforms. We identified a lead compound, UM101, that was at least as effective as SB203580 in stabilizing endothelial barrier function, reducing inflammation, and mitigating LPS-induced mouse lung injury. Differential scanning fluorimetry and saturation transfer difference-nuclear magnetic resonance demonstrated specific binding of UM101 to the computer-aided drug design-targeted pockets in p38α but not p38β. RNA sequencing analysis of TNF-α-stimulated gene expression revealed that UM101 inhibited only 28 of 61 SB203580-inhibited genes and 7 of 15 SB203580-inhibited transcription factors, but spared the anti-inflammatory MSK1/2 pathway. We provide proof of principle that small molecules that target the ED substrate-docking site may exert anti-inflammatory effects similar to the catalytic p38 inhibitors, but their isoform specificity and substrate selectivity may confer inherent advantages over catalytic inhibitors for treating inflammatory diseases.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.