Journal article
The Lck inhibitor, AMG-47a, blocks necroptosis and implicates RIPK1 in signalling downstream of MLKL
AV Jacobsen, CL Pierotti, KN Lowes, AE Au, Y Zhang, N Etemadi, C Fitzgibbon, WJA Kersten, AL Samson, MF van Delft, DCS Huang, HJ Sabroux, G Lessene, J Silke, JM Murphy
Cell Death and Disease | SPRINGERNATURE | Published : 2022
Abstract
Necroptosis is a form of caspase-independent programmed cell death that arises from disruption of cell membranes by the mixed lineage kinase domain-like (MLKL) pseudokinase after its activation by the upstream kinases, receptor interacting protein kinase (RIPK)-1 and RIPK3, within a complex known as the necrosome. Dysregulated necroptosis has been implicated in numerous inflammatory pathologies. As such, new small molecule necroptosis inhibitors are of great interest, particularly ones that operate downstream of MLKL activation, where the pathway is less well defined. To better understand the mechanisms involved in necroptosis downstream of MLKL activation, and potentially uncover new target..
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Awarded by Australian Government
Funding Acknowledgements
kThis work was funded by Australian National Health and Medical Research Council (NHMRC) grants (1046984, 1067289, 1105023, 1124735, 1124737 and 2002965) and fellowships (JMM: 1105754, 1172929; JS: 1058190,1107149; GL: 1117089; DCSH: 1156024); Anaxis Pharma Pty Ltd for funding support; and was made possible through Victorian State Government Operational Infrastructure Support, NHMRC IRIISS grant (9000719) and Australian Cancer Research Foundation funding. AVJ and CLP were supported by an Australian Government Research Training Program Stipend Scholarship. WEHI's screening facility is supported by Therapeutic Innovation Australia (TIA). TIA is supported by the Australian Government through the National Collaborative Research Infrastructure Strategy (NCRIS) program.