WHI-P131 is an inhibitor of Janus kinase 3 (JAK3) with IC₅₀ values of 9 and 78 μM against human and mouse proteins, respectively (Sudbeck et al.). It has also been reported to show significant inhibition of other kinases, including epidermal growth factor receptor (EGFR) in the nanomolar range (Changelian et al.; Uckun et al.). No significant inhibition of JAK1 or JAK2 has been observed (Sudbeck et al.).
CANCER RESEARCH
· Induces apoptosis and cell death in human glioblastoma cell lines U373 and U87 (Narla et al.).
IMMUNOLOGY
· Inhibits lipopolysaccharide (LPS)-induced nitric oxide synthase expression and nitric oxide production in macrophages (Sareila et al.).
MAINTENANCE
· Inhibits proliferation of neural stem cell-containing neurospheres at lower concentrations than the concentration required to inhibit proliferation of astrocyte cultures (Diamandis et al.).
CANCER RESEARCH
· Induces apoptosis and cell death in human glioblastoma cell lines U373 and U87 (Narla et al.).
IMMUNOLOGY
· Inhibits lipopolysaccharide (LPS)-induced nitric oxide synthase expression and nitric oxide production in macrophages (Sareila et al.).
MAINTENANCE
· Inhibits proliferation of neural stem cell-containing neurospheres at lower concentrations than the concentration required to inhibit proliferation of astrocyte cultures (Diamandis et al.).
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Protocols and Documentation
Find supporting information and directions for use in the Product Information Sheet or explore additional protocols below.
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Resources and Publications
Educational Materials (3)
Publications (6)
The specificity of JAK3 kinase inhibitors. Blood 2008
Abstract
PF-956980 is a selective inhibitor of JAK3, related in structure to CP-690550, a compound being evaluated in clinical trials for rheumatoid arthritis and prevention of allograft rejection. PF-956980 has been evaluated against a panel of 30 kinases, and found to have nanomolar potency against only JAK3. Cellular and whole blood activity of this compound parallels its potency and selectivity in enzyme assays. It was effective in vivo at inhibiting the delayed type hypersensivity reaction in mice. We compared 2 commercially available JAK3 inhibitors (WHI-P131 and WHI-P154) in the same panel of biochemical and cellular assays and found them to be neither potent nor selective for JAK3. Both were found to be nanomolar inhibitors of the EGF receptor family of kinases. As these compounds have been used in numerous publications in the transplant and autoimmune disease literature, their specificity should be considered when interpreting these results.
Janus kinase 3 inhibitor WHI-P154 in macrophages activated by bacterial endotoxin: differential effects on the expression of iNOS, COX-2 and TNF-alpha. International immunopharmacology 2008
Abstract
Bacterial endotoxin is a potent inducer of inflammatory response, including the induction of inducible nitric oxide synthase (iNOS) expression and nitric oxide (NO) production, and the expression of cyclo-oxygenase (COX)-2 and tumor necrosis factor (TNF)-alpha in inflammatory cells. In the present study, we investigated the effects of pharmacological inhibition of Janus kinase (JAK) 3 on the production of these proinflammatory molecules in macrophages exposed to bacterial endotoxin (lipopolysaccharide; LPS). JAK3 inhibitors WHI-P154 (4-(3'-bromo-4'-hydroxylphenyl)-amino-6,7-dimethoxyquinazoline) and its derivative WHI-P131 inhibited LPS-induced iNOS expression and NO production in a dose-dependent manner. WHI-P154 inhibited the activation of signal transducer and activator of transcription (STAT) 1 and the expression of iNOS mRNA but it had no effect on iNOS mRNA decay when determined by actinomycin D assay. The JAK3 inhibitor had no effect on COX-2 expression, and TNF-alpha production was slightly inhibited only at higher drug concentrations (30 microM). In addition, WHI-P154 inhibited iNOS expression and NO production also in human epithelial cells. Our results suggest that JAK3 inhibition modulates human and murine iNOS expression and NO production in response to inflammatory stimuli.
Chemical genetics reveals a complex functional ground state of neural stem cells. Nature chemical biology 2007
Abstract
The identification of self-renewing and multipotent neural stem cells (NSCs) in the mammalian brain holds promise for the treatment of neurological diseases and has yielded new insight into brain cancer. However, the complete repertoire of signaling pathways that governs the proliferation and self-renewal of NSCs, which we refer to as the 'ground state', remains largely uncharacterized. Although the candidate gene approach has uncovered vital pathways in NSC biology, so far only a few highly studied pathways have been investigated. Based on the intimate relationship between NSC self-renewal and neurosphere proliferation, we undertook a chemical genetic screen for inhibitors of neurosphere proliferation in order to probe the operational circuitry of the NSC. The screen recovered small molecules known to affect neurotransmission pathways previously thought to operate primarily in the mature central nervous system; these compounds also had potent inhibitory effects on cultures enriched for brain cancer stem cells. These results suggest that clinically approved neuromodulators may remodel the mature central nervous system and find application in the treatment of brain cancer.
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