ArticlePharmacology2009
SD0006: a potent, selective and orally available inhibitor of p38 kinase.
Article in Pharmacology, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 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
12 citing papers in PubMed.
- p38MAPKα Stromal Reprogramming Sensitizes Metastatic Breast Cancer to Immunotherapy.Cancer discovery · 2023Article
- Selective Inhibition of the MK2 Pathway: Data From a Phase IIa Randomized Clinical Trial in Rheumatoid Arthritis.ACR open rheumatology · 2023Article
- Evaluation of the therapeutic potential of the selective p38 MAPK inhibitor Skepinone-L and the dual p38/JNK 3 inhibitor LN 950 in experimental K/BxN serum transfer arthritis.Inflammopharmacology · 2019Article
- Inhibition of the Stromal p38MAPK/MK2 Pathway Limits Breast Cancer Metastases and Chemotherapy-Induced Bone Loss.Cancer research · 2018Article
- Selective inhibition of the p38α MAPK-MK2 axis inhibits inflammatory cues including inflammasome priming signals.The Journal of experimental medicine · 2018Article
- p38 MAPK inhibits nonsense-mediated RNA decay in response to persistent DNA damage in noncycling cells.The Journal of biological chemistry · 2017Article
- Suppression of cytokine production by glucocorticoids is mediated by MKP-1 in human lung epithelial cells.Inflammation research : official journal of the European Histamine Research Society ... [et al.] · 2017Article
- Anti-Inflammatory Effects of β2-Receptor Agonists Salbutamol and Terbutaline Are Mediated by MKP-1.PloS one · 2016Article
- p38MAPK plays a crucial role in stromal-mediated tumorigenesis.Cancer discovery · 2014Article
- Dual specificity phosphatase 1 regulates human inducible nitric oxide synthase expression by p38 MAP kinase.Mediators of inflammation · 2011Article
- Effects of p38 MAPK inhibition on early stages of diabetic retinopathy and sensory nerve function.Investigative ophthalmology & visual science · 2010Article
- Optical tomographic imaging discriminates between disease-modifying anti-rheumatic drug (DMARD) and non-DMARD efficacy in collagen antibody-induced arthritis.Arthritis research & therapy · 2010Article
Corrections and comments
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Authors and funding
21 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
SD0006 is a diarylpyrazole that was prepared as an inhibitor of p38 kinase-alpha (p38alpha). In vitro, SD0006 was selective for p38alpha kinase over 50 other kinases screened (including p38gamma and p38delta with modest selectivity over p38beta). Crystal structures with p38alpha show binding at the ATP site with additional residue interactions outside the ATP pocket unique to p38alpha that can confer advantages over other ATP competitive inhibitors. Direct correlation between inhibition of p38alpha activity and that of lipopolysaccharide-stimulated TNFalpha release was established in cellular models and in vivo, including a phase 1 clinical trial. Potency (IC(50)) for inhibiting tumor necrosis factor-alpha (TNFalpha) release, in vitro and in vivo, was <200 nmol/l. In vivo, SD0006 was effective in the rat streptococcal-cell-wall-induced arthritis model, with dramatic protective effects on paw joint integrity and bone density as shown by radiographic analysis. In the murine collagen-induced arthritis model, equivalence was demonstrated to anti-TNFalpha treatment. SD0006 also demonstrated good oral anti-inflammatory efficacy with excellent cross-species correlation between the rat, cynomolgus monkey, and human. SD0006 suppressed expression of multiple proinflammatory proteins at both the transcriptional and translational levels. These properties suggest SD0006 could provide broader therapeutic efficacy than cytokine-targeted monotherapeutics.
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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.