دورية أكاديمية
Characterization of GSK′963: a structurally distinct, potent and selective inhibitor of RIP1 kinase
| العنوان: | Characterization of GSK′963: a structurally distinct, potent and selective inhibitor of RIP1 kinase |
|---|---|
| المؤلفون: | Berger, SB, Harris, P, Nagilla, R, Kasparcova, V, Hoffman, S, Swift, B, Dare, L, Schaeffer, M, Capriotti, C, Ouellette, M, King, BW, Wisnoski, D, Cox, J, Reilly, M, Marquis, RW, Bertin, J, Gough, PJ |
| المصدر: | Cell Death Discovery ; volume 1, issue 1 ; ISSN 2058-7716 |
| بيانات النشر: | Springer Science and Business Media LLC |
| سنة النشر: | 2015 |
| مصطلحات موضوعية: | Cancer Research, Cell Biology, Cellular and Molecular Neuroscience, Immunology |
| الوصف: | Necroptosis and signaling regulated by RIP1 kinase activity is emerging as a key driver of inflammation in a variety of disease settings. A significant amount has been learned about how RIP1 regulates necrotic cell death through the use of the RIP1 kinase inhibitor Necrostatin-1 (Nec-1). Nec-1 has been a transformational tool for exploring the function of RIP1 kinase activity; however, its utility is somewhat limited by moderate potency, off-target activity against indoleamine-2,3-dioxygenase (IDO), and poor pharmacokinetic properties. These limitations of Nec-1 have driven an effort to identify next-generation tools to study RIP1 function, and have led to the identification of 7-Cl-O-Nec-1 (Nec-1s), which has improved pharmacokinetic properties and lacks IDO inhibitory activity. Here we describe the characterization of GSK′963, a chiral small-molecule inhibitor of RIP1 kinase that is chemically distinct from both Nec-1 and Nec-1s. GSK′963 is significantly more potent than Nec-1 in both biochemical and cellular assays, inhibiting RIP1-dependent cell death with an IC 50 of between 1 and 4 nM in human and murine cells. GSK′963 is >10 000-fold selective for RIP1 over 339 other kinases, lacks measurable activity against IDO and has an inactive enantiomer, GSK′962, which can be used to confirm on-target effects. The increased in vitro potency of GSK′963 also translates in vivo , where GSK′963 provides much greater protection from hypothermia at matched doses to Nec-1, in a model of TNF-induced sterile shock. Together, we believe GSK′963 represents a next-generation tool for examining the function of RIP1 in vitro and in vivo , and should help to clarify our current understanding of the role of RIP1 in contributing to disease pathogenesis. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| DOI: | 10.1038/cddiscovery.2015.9 |
| الإتاحة: | https://doi.org/10.1038/cddiscovery.2015.9Test https://www.nature.com/articles/cddiscovery20159.pdfTest https://www.nature.com/articles/cddiscovery20159Test |
| حقوق: | https://creativecommons.org/licenses/by/4.0Test ; https://creativecommons.org/licenses/by/4.0Test |
| رقم الانضمام: | edsbas.11C1008C |
| قاعدة البيانات: | BASE |
| DOI: | 10.1038/cddiscovery.2015.9 |
|---|