Potent inhibition of necroptosis by simultaneously targeting multiple effectors of the pathway
- Pierotti, CL; Tanzer, MC; Jacobsen, AV; Hildebrand, JM; GARNIER, JM; Sharma, P; Lucet, IS; Cowan, AD; Kersten, WJA; Luo, MX; Liang, LY; Fitzgibbon, C; Garnish, SE; Hempel, A; Nachbur, U; Huang, DCS; Czabotar, PE; Silke, J; van Delft, MF; Murphy, JM; Lessene, G;
Publication Year 2020-09-22, Volume 15, Issue #19, Page 2702-2713
- Journal Title
- ACS Chemical Biology
- Publication Type
- Journal epub ahead of print
- Necroptosis is an inflammatory form of programmed cell death that has been implicated in various human diseases. Compound 2 is a more potent analogue of the published compound 1 and inhibits necroptosis in human and murine cells at nanomolar concentrations. Several target engagement strategies were employed, including cellular thermal shift assays (CETSA) and diazirine-mediated photoaffinity labeling via a bifunctional photoaffinity probe derived from compound 2. These target engagement studies demonstrate that compound 2 binds to all three necroptotic effector proteins (mixed lineage kinase domain-like protein (MLKL), receptor-interacting serine/threonine protein kinase 1 (RIPK1) and receptor-interacting serine/threonine protein kinase 3 (RIPK3)) at different levels in vitro and in cells. Compound 2 also shows efficacy in vivo in a murine model of systemic inflammatory response syndrome (SIRS).
- WEHI Research Division(s)
- Structural Biology; Blood Cells And Blood Cancer; Inflammation; Chemical Biology
- PubMed ID
- Publisher's Version
- Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2020-10-17 02:40:37Last Modified: 2020-11-03 10:20:37