A highly selective ATP site-targeting inhibitor against human/monkey, but not non-primate, RIP1.
GSK′481 is a highly potent receptor interacting protein 1 kinase (RIP1, RIPK1) inhibitor (human/monkey RIP1 IC50 = 1.6/2.5 nM; [ATP] = 50 μM) that targets RIP1 ATP-binding pocket with high affinity (kon = 0.66/μM/sec, t1/2 = 11 min) with little potency toward non-primate RIP1 (IC50 = 2.0/3.2/6.3/7.9/>10 μM against rabbit/mouse/rat/dog/minipig RIP1) and no off-target affinity when profiled at 10 μM by a 456-kinase panel. GSK′481 blocks caspase inhibitor/TNF-induced necroptosis in human monocytic U937 cultures (IC50 = 10 nM) and inhibits S166 autophosphorylation of exogenously expressed human, but not mouse, RIP1 in HEK293T transfectants (IC50 = 2.8 nM and >10 μM, respectively).
Acquired or intrinsic resistance to apoptotic and necroptotic stimuli is considered a major hindrance of therapeutic success in malignant melanoma. Inhibitor of apoptosis proteins (IAPs) are important regulators of apoptotic and necroptotic cell death mediated by numerous cell death signalling
Pharmacology research & perspectives, 5(6) (2017-12-12)
Therapies that suppress RIPK1 kinase activity are emerging as promising therapeutic agents for the treatment of multiple inflammatory disorders. The ability to directly measure drug binding of a RIPK1 inhibitor to its target is critical for providing insight into pharmacokinetics
Journal of medicinal chemistry, 59(5), 2163-2178 (2016-02-09)
The recent discovery of the role of receptor interacting protein 1 (RIP1) kinase in tumor necrosis factor (TNF)-mediated inflammation has led to its emergence as a highly promising target for the treatment of multiple inflammatory diseases. We screened RIP1 against
Influenza A virus (IAV) is a lytic virus in primary cultures of many cell types and in vivo. We report that the kinase RIPK3 is essential for IAV-induced lysis of mammalian fibroblasts and lung epithelial cells. Replicating IAV drives assembly of
Methods (San Diego, Calif.), 134-135, 56-66 (2017-11-28)
Flow cytometry was been widely used to measure apoptosis for many decades but the researcher has no definitive way of determining other forms of cell death using this technology. The use of Western Blot technology has numerous drawbacks in that
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