Vemurafenib inhibits necroptosis in normal and pathological conditions as a RIPK1 antagonist.
Journal
Cell death & disease
ISSN: 2041-4889
Titre abrégé: Cell Death Dis
Pays: England
ID NLM: 101524092
Informations de publication
Date de publication:
24 08 2023
24 08 2023
Historique:
received:
29
03
2023
accepted:
14
08
2023
revised:
01
08
2023
medline:
28
8
2023
pubmed:
25
8
2023
entrez:
24
8
2023
Statut:
epublish
Résumé
Necroptosis, a programmed cell death with necrotic-like morphology, has been recognized as an important driver in various inflammatory diseases. Inhibition of necroptosis has shown potential promise in the therapy of multiple human diseases. However, very few necroptosis inhibitors are available for clinical use as yet. Here, we identified an FDA-approved anti-cancer drug, Vemurafenib, as a potent inhibitor of necroptosis. Through direct binding, Vemurafenib blocked the kinase activity of receptor-interacting protein kinases 1 (RIPK1), impeded the downstream signaling and necrosome complex assembly, and inhibited necroptosis. Compared with Necrostain-1, Vemurafenib stabilized RIPK1 in an inactive DLG-out conformation by occupying a distinct allosteric hydrophobic pocket. Furthermore, pretreatment with Vemurafenib provided strong protection against necroptosis-associated diseases in vivo. Altogether, our results demonstrate that Vemurafenib is an effective RIPK1 antagonist and provide rationale and preclinical evidence for the potential application of approved drug in necroptosis-related diseases.
Identifiants
pubmed: 37620300
doi: 10.1038/s41419-023-06065-8
pii: 10.1038/s41419-023-06065-8
pmc: PMC10449909
doi:
Substances chimiques
Receptor-Interacting Protein Serine-Threonine Kinases
EC 2.7.11.1
RIPK1 protein, human
EC 2.7.11.1
Vemurafenib
207SMY3FQT
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
555Informations de copyright
© 2023. The Author(s).
Références
N Engl J Med. 2010 Aug 26;363(9):809-19
pubmed: 20818844
Oncol Lett. 2012 Jan;3(1):16-18
pubmed: 22740848
Clin Pharmacokinet. 2017 Sep;56(9):1033-1043
pubmed: 28255850
Trends Pharmacol Sci. 2020 Mar;41(3):209-224
pubmed: 32035657
Cell Death Discov. 2015 Jul 27;1:15009
pubmed: 27551444
J Med Chem. 2017 Feb 23;60(4):1247-1261
pubmed: 28151659
Cell. 2003 Jul 25;114(2):181-90
pubmed: 12887920
Cell Death Differ. 2016 Oct;23(10):1628-37
pubmed: 27258786
Nat Rev Drug Discov. 2012 Nov;11(11):873-86
pubmed: 23060265
Bioinformatics. 2012 Jan 15;28(2):286-7
pubmed: 22113084
Cell Res. 2013 Aug;23(8):994-1006
pubmed: 23835476
Cell Death Differ. 2016 Sep 1;23(9):1428-47
pubmed: 26943325
Pharmacol Res. 2021 Jan;163:105297
pubmed: 33181319
Nat Cell Biol. 2022 Apr;24(4):471-482
pubmed: 35256774
J Comput Chem. 2013 Jan 5;34(1):67-75
pubmed: 22961860
Cell Death Differ. 2014 Oct;21(10):1511-21
pubmed: 24902904
Nat Rev Mol Cell Biol. 2013 Nov;14(11):727-36
pubmed: 24129419
Trends Cancer. 2022 Jan;8(1):21-27
pubmed: 34627742
Mol Cell. 2020 Oct 15;80(2):296-310.e6
pubmed: 32979304
Nature. 2016 Aug 11;536(7615):215-8
pubmed: 27487218
Cell Mol Gastroenterol Hepatol. 2016 Jul;2(4):519-535
pubmed: 27642624
J Dermatol. 2021 Aug;48(8):1129-1138
pubmed: 34109676
Immunity. 2011 Dec 23;35(6):908-18
pubmed: 22195746
Cell Death Differ. 2012 Jan;19(1):75-86
pubmed: 22075985
Cell Death Dis. 2015 May 21;6:e1767
pubmed: 25996294
Br J Pharmacol. 2019 Jun;176(12):2095-2108
pubmed: 30825190
Oncologist. 2015 Aug;20(8):847-8
pubmed: 26173838
Cell. 2009 Jun 12;137(6):1100-11
pubmed: 19524512
Cell Death Dis. 2015 Sep 10;6:e1884
pubmed: 26355347
Nat Rev Neurosci. 2019 Jan;20(1):19-33
pubmed: 30467385
Nat Commun. 2017 Aug 25;8(1):359
pubmed: 28842570
Ann Transl Med. 2022 Nov;10(22):1214
pubmed: 36544673
Proc Natl Acad Sci U S A. 2008 Feb 26;105(8):3041-6
pubmed: 18287029
Structure. 2013 Mar 5;21(3):493-9
pubmed: 23473668
J Biol Chem. 2013 Mar 29;288(13):9145-52
pubmed: 23386613
Cell. 2012 Jan 20;148(1-2):213-27
pubmed: 22265413
Cell. 2009 Jun 12;137(6):1112-23
pubmed: 19524513
Nat Chem Biol. 2005 Jul;1(2):112-9
pubmed: 16408008
Science. 2009 Jul 17;325(5938):332-6
pubmed: 19498109
Mol Med Rep. 2021 Nov;24(5):
pubmed: 34498705
Cell. 1995 May 19;81(4):513-23
pubmed: 7538908
Exp Mol Med. 2019 Aug 2;51(8):1-17
pubmed: 31375658
Immunity. 2013 Feb 21;38(2):209-23
pubmed: 23438821
Nat Rev Mol Cell Biol. 2010 Oct;11(10):700-14
pubmed: 20823910
Future Oncol. 2011 Oct;7(10):1223-35
pubmed: 21992733
Cell Death Dis. 2014 Jun 05;5:e1278
pubmed: 24901049
Nat Chem Biol. 2008 May;4(5):313-21
pubmed: 18408713
Cell Death Dis. 2017 Jun 29;8(6):e2904
pubmed: 28661484
Cells. 2021 Apr 27;10(5):
pubmed: 33925729
Nat Cell Biol. 2014 Jan;16(1):55-65
pubmed: 24316671
J Cell Biol. 2021 Jun 7;220(6):
pubmed: 33914027
Nat Chem Biol. 2015 Nov;11(11):818-21
pubmed: 26485069
Mol Cancer. 2019 May 23;18(1):100
pubmed: 31122251