ArticleCell chemical biology2023
Inhibition of a lower potency target drives the anticancer activity of a clinical p38 inhibitor.
Article in Cell chemical biology, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
18 citing papers in PubMed, 24 citations in OpenAlex.
- POLB 001, a p38 MAPK inhibitor, decreases local and systemic inflammatory responses followingFrontiers in immunology · 2025Trial
- Advances in targeting p38 MAPK for cancer therapy: insights from molecular pharmacology and medicinal chemistry.Molecular diversity · 2026Review
- Role of the ETV5/p38 Signaling Axis in Aggressive Thyroid Cancer Cells.Molecular cancer therapeutics · 2026Article
- Targeting p38α in cancer: challenges, opportunities, and emerging strategies.Molecular oncology · 2026Review
- A clinical-stage oncology compound selectively targets drug-resistant cancers.bioRxiv : the preprint server for biology · 2026Article
- Structural Studies of Fourth-Generation EGFR Inhibitors Reveal Insights into Selective T790M and C797S Targeting.ACS medicinal chemistry letters · 2026Article
- Informing development of brain cancer therapies within "preclinical trials" using ex vivo patient tumors.Advanced drug delivery reviews · 2026Review
- DUSP8 as a regulator of glioblastoma stem-like cell contribution to tumor vascularization.Journal of experimental & clinical cancer research : CR · 2025Article
- Profiling and Optimizing Targeted Covalent Inhibitors through EGFR-Guided Studies.Journal of medicinal chemistry · 2025Article
- Desmoglein-driven dynamic signaling in pemphigus vulgaris: a systematic review of pathogenic pathways.NPJ Regenerative medicine · 2025Article
- Cancer-on-a-chip for precision cancer medicine.Lab on a chip · 2025Review
- Ascertaining a Structural Basis in Drug Discovery and Development.Journal of medicinal chemistry · 2025Article
- Tilting the Scales toward EGFR Mutant Selectivity: Expanding the Scope of Bivalent "Type V" Kinase Inhibitors.Journal of medicinal chemistry · 2024Article
- Demystifying Functional Parameters for Irreversible Enzyme Inhibitors.Journal of medicinal chemistry · 2024Article
- Multi-Omic Analysis: A Possible Platform Toward Personalized and Adaptable Cancer Treatment.Annals of surgical oncology · 2024Article
- Translation of Epigenetics in Cell-Free DNA Liquid Biopsy Technology and Precision Oncology.Current issues in molecular biology · 2024Review
- An integrative epigenome-based strategy for unbiased functional profiling of clinical kinase inhibitors.Molecular systems biology · 2024Article
- Review
Corrections and comments
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Authors and funding
10 authors at 5 institutions in 1 country.
Funding
Abstract
The small-molecule drug ralimetinib was developed as an inhibitor of the p38α mitogen-activated protein kinase, and it has advanced to phase 2 clinical trials in oncology. Here, we demonstrate that ralimetinib resembles EGFR-targeting drugs in pharmacogenomic profiling experiments and that ralimetinib inhibits EGFR kinase activity in vitro and in cellulo. While ralimetinib sensitivity is unaffected by deletion of the genes encoding p38α and p38β, its effects are blocked by expression of the EGFR-T790M gatekeeper mutation. Finally, we solved the cocrystal structure of ralimetinib bound to EGFR, providing further evidence that this drug functions as an ATP-competitive EGFR inhibitor. We conclude that, though ralimetinib is >30-fold less potent against EGFR compared to p38α, its ability to inhibit EGFR drives its primary anticancer effects. Our results call into question the value of p38α as an anticancer target, and we describe a multi-modal approach that can be used to uncover a drug's mechanism-of-action.
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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.