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

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

doi:10.1021/acschembio.0c00482

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

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

Guillaume Lessene (Lead / Corresponding author)

Biological Chemistry and Drug Discovery

Research output: Contribution to journal › Article › peer-review

31 Citations (Scopus)

Abstract

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).

Original language	English
Pages (from-to)	2702-2713
Number of pages	12
Journal	ACS Chemical Biology
Volume	15
Issue number	10
Early online date	9 Sept 2020
DOIs	https://doi.org/10.1021/acschembio.0c00482
Publication status	Published - 16 Oct 2020

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

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Pierotti, C. L., Tanzer, M. C., Jacobsen, A. V., Hildebrand, J. M., Garnier, J.-M., Sharma, P., Lucet, I. S., Cowan, A. D., Kersten, W. J. A., Luo, M.-X., Liang, L.-Y., Fitzgibbon, C., Garnish, S. E., Hempel, A., Nachbur, U., Huang, D. C. S., Czabotar, P. E., Silke, J., van Delft, M. F., ... Lessene, G. (2020). Potent Inhibition of Necroptosis by Simultaneously Targeting Multiple Effectors of the Pathway. ACS Chemical Biology, 15(10), 2702-2713. https://doi.org/10.1021/acschembio.0c00482

@article{31a1c67557184142bb9072cfe7014eb8,

title = "Potent Inhibition of Necroptosis by Simultaneously Targeting Multiple Effectors of the Pathway",

abstract = "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).",

author = "Pierotti, \{Catia L.\} and Tanzer, \{Maria C.\} and Jacobsen, \{Annette V.\} and Hildebrand, \{Joanne M.\} and Jean-Marc Garnier and Pooja Sharma and Lucet, \{Isabelle S.\} and Cowan, \{Angus D.\} and Kersten, \{Wilhelmus J. A.\} and Meng-Xiao Luo and Lung-Yu Liang and Cheree Fitzgibbon and Garnish, \{Sarah E.\} and Anne Hempel and Ueli Nachbur and Huang, \{David C. S.\} and Czabotar, \{Peter E.\} and John Silke and \{van Delft\}, \{Mark F.\} and Murphy, \{James M.\} and Guillaume Lessene",

year = "2020",

month = oct,

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doi = "10.1021/acschembio.0c00482",

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Pierotti, CL, Tanzer, MC, Jacobsen, AV, Hildebrand, JM, Garnier, J-M, Sharma, P, Lucet, IS, Cowan, AD, Kersten, WJA, Luo, M-X, Liang, L-Y, Fitzgibbon, C, Garnish, SE, Hempel, A, Nachbur, U, Huang, DCS, Czabotar, PE, Silke, J, van Delft, MF, Murphy, JM & Lessene, G 2020, 'Potent Inhibition of Necroptosis by Simultaneously Targeting Multiple Effectors of the Pathway', ACS Chemical Biology, vol. 15, no. 10, pp. 2702-2713. https://doi.org/10.1021/acschembio.0c00482

TY - JOUR

T1 - Potent Inhibition of Necroptosis by Simultaneously Targeting Multiple Effectors of the Pathway

AU - Pierotti, Catia L.

AU - Tanzer, Maria C.

AU - Jacobsen, Annette V.

AU - Hildebrand, Joanne M.

AU - Garnier, Jean-Marc

AU - Sharma, Pooja

AU - Lucet, Isabelle S.

AU - Cowan, Angus D.

AU - Kersten, Wilhelmus J. A.

AU - Luo, Meng-Xiao

AU - Liang, Lung-Yu

AU - Fitzgibbon, Cheree

AU - Garnish, Sarah E.

AU - Hempel, Anne

AU - Nachbur, Ueli

AU - Huang, David C. S.

AU - Czabotar, Peter E.

AU - Silke, John

AU - van Delft, Mark F.

AU - Murphy, James M.

AU - Lessene, Guillaume

PY - 2020/10/16

Y1 - 2020/10/16

N2 - 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).

AB - 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).

UR - https://www.scopus.com/pages/publications/85093538270

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DO - 10.1021/acschembio.0c00482

M3 - Article

SN - 1554-8929

VL - 15

SP - 2702

EP - 2713

JO - ACS Chemical Biology

JF - ACS Chemical Biology

IS - 10

ER -

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

Abstract

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