ArticlePharmacology research & perspectives2015
In vitro pharmacological profiling of R406 identifies molecular targets underlying the clinical effects of fostamatinib.
Article in Pharmacology research & perspectives, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 54 papers.
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Who cites it
54 citing papers in PubMed.
- Fostamatinib for the treatment of adult persistent and chronic immune thrombocytopenia: Results of two phase 3, randomized, placebo-controlled trials.American journal of hematology · 2018Trial
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- IIC-DTI: A Contrastive Learning Enhanced Inter-Intra Molecular Fusing Framework for Drug-Target Interaction Prediction.Interdisciplinary sciences, computational life sciences · 2026Article
- The perinecrotic niche of glioblastoma drives tumor-associated macrophage polarization and immunosuppression via podoplanin-mediated CLEC5A activation.The Journal of clinical investigation · 2026Article
- MiR-31 suppresses lung adenocarcinoma cell proliferation through CDK1 and E2F2-mediated cell cycle arrest.Discover oncology · 2026Article
- Fostamatinib (R788), a spleen tyrosine kinase inhibitor, sensitizes pancreatic cancer cells to oncolytic vesicular stomatitis virus.Molecular therapy. Oncology · 2025Article
- Fostamatinib and the risk of acute aortic dissection in immune thrombocytopenia.British journal of clinical pharmacology · 2025Article
- Network Controllability Reveals Key Mitigation Points for Tumor-Promoting Signaling in Tumor-Educated Platelets.International journal of molecular sciences · 2025Article
- Spatiotemporal interaction of immune and renal cells controls glomerular crescent formation in autoimmune kidney disease.Nature immunology · 2025Article
- Systematic druggable genome-wide Mendelian randomization identifies therapeutic targets for calcium pyrophosphate deposition disease.Clinical rheumatology · 2025Article
- Integrating QSAR modelling with reinforcement learning for Syk inhibitor discovery.Journal of cheminformatics · 2025Article
- SHIP-1 Differentially Regulates IgE-Induced IL-10 and Antiviral Responses in Human Monocytes.European journal of immunology · 2025Article
- A novel small molecule phagocytosis inhibitor, KB-208, ameliorates ITP in mouse models with similar efficacy as IVIG.Transfusion · 2024Article
- Accelerated hit identification with target evaluation, deep learning and automated labs: prospective validation in IRAK1.Journal of cheminformatics · 2024Article
- Analyses of GWAS signal using GRIN identify additional genes contributing to suicidal behavior.Communications biology · 2024Article
- Tumor-intrinsic CDC42BPB confers resistance to anti-PD-1 immune checkpoint blockade in breast cancer.Molecular therapy : the journal of the American Society of Gene Therapy · 2024Article
- Non-kinase off-target inhibitory activities of clinically-relevant kinase inhibitors.European journal of medicinal chemistry · 2024Review
- Discovery of Sovleplenib, a Selective Inhibitor of Syk in Clinical Development for Autoimmune Diseases and Cancers.ACS medicinal chemistry letters · 2024Article
- Proteome-Wide Mendelian Randomization and Colocalization Analysis Identify Therapeutic Targets for Knee and Hip Osteoarthritis.Biomolecules · 2024Article
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Authors and funding
8 authors.
Funding
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Abstract
Off-target pharmacology may contribute to both adverse and beneficial effects of a new drug. In vitro pharmacological profiling is often applied early in drug discovery; there are fewer reports addressing the relevance of broad profiles to clinical adverse effects. Here, we have characterized the pharmacological profile of the active metabolite of fostamatinib, R406, linking an understanding of drug selectivity to the increase in blood pressure observed in clinical studies. R406 was profiled in a broad range of in vitro assays to generate a comprehensive pharmacological profile and key targets were further investigated using functional and cellular assay systems. A combination of traditional literature searches and text-mining approaches established potential mechanistic links between the profile of R406 and clinical side effects. R406 was selective outside the kinase domain, with only antagonist activity at the adenosine A3 receptor in the range relevant to clinical effects. R406 was less selective in the kinase domain, having activity at many protein kinases at therapeutically relevant concentrations when tested in multiple in vitro systems. Systematic literature analyses identified KDR as the probable target underlying the blood pressure increase observed in patients. While the in vitro pharmacological profile of R406 suggests a lack of selectivity among kinases, a combination of classical searching and text-mining approaches rationalized the complex profile establishing linkage between off-target pharmacology and clinically observed effects. These results demonstrate the utility of in vitro pharmacological profiling for a compound in late-stage clinical development.
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