Allosteric Inhibition of c-Abl to Induce Unfolded Protein Response and Cell Death in Multiple Myeloma.
GNF-2
IRE1α
asciminib
c-Abl
multiple myeloma
unfolded protein response
Journal
International journal of molecular sciences
ISSN: 1422-0067
Titre abrégé: Int J Mol Sci
Pays: Switzerland
ID NLM: 101092791
Informations de publication
Date de publication:
18 Dec 2022
18 Dec 2022
Historique:
received:
16
10
2022
revised:
03
12
2022
accepted:
15
12
2022
entrez:
23
12
2022
pubmed:
24
12
2022
medline:
27
12
2022
Statut:
epublish
Résumé
Endoplasmic reticulum stress activates inositol-requiring enzyme 1α (IRE1α) and protein kinase, R-like endoplasmic reticulum kinase (PERK), the two principal regulators of the unfolded protein response (UPR). In multiple myeloma, adaptive IRE1α signaling is predominantly activated and regulates cell fate along with PERK. Recently, we demonstrated that GNF-2, an allosteric c-Abl inhibitor, rheostatically enhanced IRE1α activity and induced apoptosis through c-Abl conformational changes in pancreatic β cells. Herein, we analyzed whether the pharmacological modulation of c-Abl conformation resulted in anti-myeloma effects. First, we investigated the effects of GNF-2 on IRE1α activity and cell fate, followed by an investigation of the anti-myeloma effects of asciminib, a new allosteric c-Abl inhibitor. Finally, we performed RNA sequencing to characterize the signaling profiles of asciminib. We observed that both GNF-2 and asciminib decreased cell viability and induced
Identifiants
pubmed: 36555805
pii: ijms232416162
doi: 10.3390/ijms232416162
pmc: PMC9786043
pii:
doi:
Substances chimiques
Endoribonucleases
EC 3.1.-
Protein Serine-Threonine Kinases
EC 2.7.11.1
RNA, Messenger
0
X-Box Binding Protein 1
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : JSPS KAKENHI
ID : JP20K08718, JP20K17405, JP21K08562, JP22K16308
Organisme : Takeda Science Foundation
ID : 2021
Références
J Clin Oncol. 2019 May 10;37(14):1228-1263
pubmed: 30932732
J Med Chem. 2018 Sep 27;61(18):8120-8135
pubmed: 30137981
Int J Hematol. 2021 May;113(5):632-641
pubmed: 33772728
N Engl J Med. 2019 Dec 12;381(24):2315-2326
pubmed: 31826340
Blood. 2008 Aug 15;112(4):1346-56
pubmed: 18524994
Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50
pubmed: 16199517
Nat Rev Clin Oncol. 2017 Mar;14(3):141-154
pubmed: 27752053
Nat Chem Biol. 2006 Feb;2(2):95-102
pubmed: 16415863
Cancers (Basel). 2021 Oct 18;13(20):
pubmed: 34680358
J Cell Sci. 2016 Jan 1;129(1):9-16
pubmed: 26729027
Leuk Lymphoma. 2006 Mar;47(3):531-9
pubmed: 16396777
Haematologica. 2013 Oct;98(10):1510-6
pubmed: 23716543
Br J Haematol. 1996 Dec;95(3):489-93
pubmed: 8943889
J Clin Invest. 2000 Jan;105(1):3-7
pubmed: 10619854
J Biol Chem. 2009 Oct 16;284(42):29005-14
pubmed: 19679652
Cancer Cell. 2020 Apr 13;37(4):530-542
pubmed: 32289275
Clin Exp Med. 2019 Feb;19(1):133-141
pubmed: 30291461
Leukemia. 2010 Aug;24(8):1506-12
pubmed: 20555361
Nature. 2017 Mar 30;543(7647):733-737
pubmed: 28329763
BMC Endocr Disord. 2020 Jun 22;20(1):90
pubmed: 32571297
Cancer Res. 2019 Dec 15;79(24):6190-6203
pubmed: 31672843
Int J Mol Sci. 2021 Jan 30;22(3):
pubmed: 33573271
Nat Genet. 2003 Jul;34(3):267-73
pubmed: 12808457
Eur J Neurosci. 2003 Jun;17(11):2287-98
pubmed: 12814362
Am J Hematol. 2022 Sep;97(9):1236-1256
pubmed: 35751859
Leukemia. 2018 Feb;32(2):252-262
pubmed: 29257139
Nat Rev Mol Cell Biol. 2020 Aug;21(8):421-438
pubmed: 32457508
Leukemia. 2017 Nov;31(11):2443-2448
pubmed: 28620163
Cell Metab. 2017 Apr 4;25(4):883-897.e8
pubmed: 28380378
Int J Mol Sci. 2020 Aug 31;21(17):
pubmed: 32878237
Cell. 2017 Feb 9;168(4):692-706
pubmed: 28187289
Nat Rev Cancer. 2021 Feb;21(2):71-88
pubmed: 33214692
Int J Mol Sci. 2019 Feb 11;20(3):
pubmed: 30754624
Br J Haematol. 2003 Dec;123(5):858-68
pubmed: 14632777
Am J Pathol. 2020 May;190(5):934-946
pubmed: 32112719
Mol Cell. 2018 Jan 18;69(2):169-181
pubmed: 29107536
Leukemia. 2022 Mar;36(3):873-876
pubmed: 34635783
Clin Lymphoma Myeloma Leuk. 2022 Jul;22(7):460-473
pubmed: 35148975