Targeting Protein Neddylation to Inactivate Cullin-RING Ligases by Gossypol: A Lucky Hit or a New Start?
anti-cancer drug
cullin-RING E3 ligases
high-throughput screen
natural product
neddylation
small-molecule inhibitors
Journal
Drug design, development and therapy
ISSN: 1177-8881
Titre abrégé: Drug Des Devel Ther
Pays: New Zealand
ID NLM: 101475745
Informations de publication
Date de publication:
2021
2021
Historique:
received:
12
10
2020
accepted:
16
12
2020
entrez:
14
1
2021
pubmed:
15
1
2021
medline:
1
10
2021
Statut:
epublish
Résumé
Cullin-RING E3 ligases (CRLs) are the largest family of E3 ubiquitin ligases, responsible for about 20% of the protein degradation by the ubiquitin-proteasome system (UPS). Given their vital roles in multiple cellular processes, and over-activation in many human cancers, CRLs are validated as promising targets for anti-cancer therapies. Activation of CRLs requires cullin neddylation, a process catalysed by three neddylation enzymes. Recently, our group established an AlphaScreen-based in vitro cullin neddylation assay and employed it for high-throughput screening to search for small-molecule inhibitors targeting cullin neddylation. During our pilot screen, gossypol, a natural product extracted from cottonseeds, was identified as one of the most potent neddylation inhibitors of cullin-1 and cullin-5. We further demonstrated that gossypol blocks cullin neddylation by binding to cullin-1/-5 to inactivate CRL1/5 ligase activity, leading to accumulation of MCL-1 and NOXA, the substrates of CRL1 and CRL5, respectively. The combination of gossypol and an MCL-1 inhibitor synergistically enhanced the anti-proliferative effect in multiple human cancer cell lines. Our study unveiled a rational combination of two previously known inhibitors of the Bcl-2 family for enhanced anti-cancer efficacy and identified a novel activity of gossypol as an inhibitor of CRL1 and CRL5 E3s, thus providing a new possibility in the development of novel CRL inhibitors for anti-cancer therapy.
Identifiants
pubmed: 33442232
doi: 10.2147/DDDT.S286373
pii: 286373
pmc: PMC7797302
doi:
Substances chimiques
CUL3 protein, human
0
Cullin Proteins
0
Enzyme Inhibitors
0
Gossypol
KAV15B369O
Types de publication
Journal Article
Review
Langues
eng
Sous-ensembles de citation
IM
Pagination
1-8Informations de copyright
© 2021 Yu and Sun.
Déclaration de conflit d'intérêts
The authors report no conflicts of interest in this work.
Références
J Med Chem. 2010 Aug 12;53(15):5502-10
pubmed: 20684596
Nature. 2011 Mar 3;471(7336):110-4
pubmed: 21368834
J Biol Chem. 2014 Jun 6;289(23):16190-9
pubmed: 24778183
Antioxid Redox Signal. 2014 Dec 10;21(17):2383-400
pubmed: 24410571
Cell Death Dis. 2011 Nov 10;2:e227
pubmed: 22071632
Nat Rev Mol Cell Biol. 2009 May;10(5):319-31
pubmed: 19352404
Breast Cancer Res Treat. 2001 Apr;66(3):239-48
pubmed: 11510695
Br J Cancer. 1997;76(1):21-8
pubmed: 9218727
Nature. 2020 Feb;578(7795):461-466
pubmed: 32051583
Nat Rev Clin Oncol. 2017 Jul;14(7):417-433
pubmed: 28117417
Nat Rev Drug Discov. 2018 May;17(5):353-377
pubmed: 29545548
Clin Genitourin Cancer. 2016 Feb;14(1):22-7
pubmed: 26476589
Nature. 2016 Oct 27;538(7626):477-482
pubmed: 27760111
Immunol Lett. 2018 Oct;202:44-51
pubmed: 30099009
Mol Cancer Ther. 2008 Jul;7(7):2192-202
pubmed: 18645028
J Clin Oncol. 2019 May 10;37(14):1228-1263
pubmed: 30932732
Proc Natl Acad Sci U S A. 2016 Apr 5;113(14):E2011-8
pubmed: 27001857
J Thorac Oncol. 2011 Oct;6(10):1757-60
pubmed: 21918390
Biochem Pharmacol. 1993 Jul 20;46(2):251-5
pubmed: 8347147
Cell Signal. 2018 Apr;44:92-102
pubmed: 29331584
Invest New Drugs. 2014 Apr;32(2):295-302
pubmed: 23860642
Neoplasia. 2020 Apr;22(4):179-191
pubmed: 32145688
Int J Mol Sci. 2016 Jun 20;17(5):
pubmed: 27331811
Adv Exp Med Biol. 1997;414:133-46
pubmed: 9059615
Biomed Res Int. 2019 Sep 29;2019:1212369
pubmed: 31662966
Nature. 2009 Apr 9;458(7239):732-6
pubmed: 19360080
Semin Cancer Biol. 2020 Dec;67(Pt 2):61-79
pubmed: 32334051
Cell Death Dis. 2015 Jan 15;6:e1593
pubmed: 25590803
Front Pharmacol. 2018 Nov 06;9:1269
pubmed: 30459622
Future Med Chem. 2017 Jul;9(11):1243-1275
pubmed: 28722469
Clin Cancer Res. 2009 May 1;15(9):3172-6
pubmed: 19366825
Nat Rev Mol Cell Biol. 2009 Nov;10(11):755-64
pubmed: 19851334
Chem Soc Rev. 2015 Nov 21;44(22):8238-59
pubmed: 26248294
Blood. 2010 Apr 22;115(16):3304-13
pubmed: 20197552
Invest New Drugs. 2019 Aug;37(4):755-762
pubmed: 31172443
Annu Rev Biochem. 2009;78:399-434
pubmed: 19489725
Annu Rev Biochem. 2017 Jun 20;86:129-157
pubmed: 28375744
Cell. 2011 Jun 24;145(7):1075-87
pubmed: 21683433
Cell Death Dis. 2020 Jul 22;11(7):556
pubmed: 32699213
Adv Med. 2014;2014:943648
pubmed: 26556430
Lancet. 2009 Jul 25;374(9686):324-39
pubmed: 19541364
Transl Res. 2018 Aug;198:1-16
pubmed: 29654740
Mol Carcinog. 1989;2(3):136-43
pubmed: 2789690
J Cell Biol. 2012 Nov 12;199(4):583-8
pubmed: 23148232
Pharm Biol. 2014 Jan;52(1):124-8
pubmed: 24073600
Annu Rev Pharmacol Toxicol. 1984;24:329-60
pubmed: 6375548
Clin Cancer Res. 2017 Feb 15;23(4):1104-1116
pubmed: 27591266
Acta Pharm Sin B. 2020 May;10(5):746-765
pubmed: 32528826
Mol Cell Biol. 2007 Jun;27(11):4006-17
pubmed: 17387146
J Cancer Res Clin Oncol. 2020 Jan;146(1):117-126
pubmed: 31844979
J Thorac Oncol. 2010 Oct;5(10):1637-43
pubmed: 20808253
J Biol Chem. 2011 Jul 15;286(28):24882-95
pubmed: 21628457
J Med Chem. 2006 Oct 19;49(21):6139-42
pubmed: 17034116
Ann Oncol. 2012 Jul;23(7):1803-8
pubmed: 22112969
Invest New Drugs. 2020 Jun;38(3):855-865
pubmed: 31388792
Cancer Chemother Pharmacol. 2015 Sep;76(3):575-86
pubmed: 26208739
J Med Chem. 2003 Sep 25;46(20):4259-64
pubmed: 13678404
Expert Opin Ther Targets. 2017 Aug;21(8):767-779
pubmed: 28670929
J Med Chem. 2008 Feb 28;51(4):717-20
pubmed: 18237106
Annu Rev Biochem. 1998;67:425-79
pubmed: 9759494
J Thorac Oncol. 2011 Apr;6(4):781-5
pubmed: 21289522
Biol Chem. 2000 Sep-Oct;381(9-10):955-9
pubmed: 11076027
Cell. 2017 May 18;169(5):792-806
pubmed: 28525752
Cancer Res. 2012 Jun 15;72(12):3069-79
pubmed: 22525702
J Med Chem. 2009 Jul 23;52(14):4119-25
pubmed: 19603832