Journal article

Potent Inhibition of Necroptosis by Simultaneously Targeting Multiple Effectors of the Pathway

Catia L Pierotti, Maria C Tanzer, Annette Jacobsen, Joanne M Hildebrand, Jean-Marc Garnier, Pooja Sharma, Isabelle S Lucet, Angus D Cowan, Wilhelmus JA Kersten, Meng-Xiao Luo, Lung-Yu Liang, Cheree Fitzgibbon, Sarah E Garnish, Anne Hempel, Ueli Nachbur, David CS Huang, Peter E Czabotar, John Silke, Mark F van Delft, James M Murphy Show all



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 recept..

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Awarded by Australian National Health and Medical Research Council (NHMRC)

Awarded by NHMRC

Awarded by NHMRC Independent Research Institutes Infrastructure Support Scheme (IRIISS)

Funding Acknowledgements

We gratefully acknowledge the following funding sources that supported this research. CLP and AVJ: Australian Government Research Training Program (RTP) Scholarship. MCT: Victorian International Research Scholarship (VIRS). JMH: Australian National Health and Medical Research Council (NHMRC) fellowship 541951. LL: Melbourne Research Scholarship (MRS). PEC: NHMRC fellowship 1079700. JS: NHMRC fellowships 1058190 and 1107149; NHMRC project grant 1057905. JMM: NHMRC fellowships 1105754 and 1172929; NHMRC project grant 1124735. GL: NHMRC fellowship 1117089; NHMRC project grant 1067289. All authors: NHMRC Independent Research Institutes Infrastructure Support Scheme (IRIISS) 9000587; Victorian State Government Operational Infrastructure Support Scheme. We also acknowledge support from the Australian Cancer Research Foundation. We gratefully thank the CSIRO C3 facility, Australian Synchrotron MX beamlines and the Walter and Eliza Hall Institute Bioservices facility. We also thank T. Ashton for assistance with analyzing NMR data and preparing the chemistry experimental.