Mechanism-based inhibitors of SIRT2: structure-activity relationship, X-ray structures, target engagement, regulation of α-tubulin acetylation and inhibition of breast cancer cell migration.
Journal
RSC chemical biology
ISSN: 2633-0679
Titre abrégé: RSC Chem Biol
Pays: England
ID NLM: 101768727
Informations de publication
Date de publication:
01 Apr 2021
01 Apr 2021
Historique:
received:
28
03
2020
accepted:
21
12
2020
entrez:
30
8
2021
pubmed:
31
8
2021
medline:
31
8
2021
Statut:
epublish
Résumé
Sirtuin 2 (SIRT2) is a protein deacylase enzyme that removes acetyl groups and longer chain acyl groups from post-translationally modified lysine residues. It affects diverse biological functions in the cell and has been considered a drug target in relation to both neurodegenerative diseases and cancer. Therefore, access to well-characterized and robust tool compounds is essential for the continued investigation of the complex functions of this enzyme. Here, we report a collection of chemical probes that are potent, selective, stable in serum, water-soluble, and inhibit SIRT2-mediated deacetylation and demyristoylation in cells. Compared to the current landscape of SIRT2 inhibitors, this is a unique ensemble of features built into a single compound. We expect the developed chemotypes to find broad application in the interrogation of SIRT2 functions in both healthy and diseased cells, and to provide a foundation for the development of future therapeutics.
Identifiants
pubmed: 34458803
doi: 10.1039/d0cb00036a
pii: d0cb00036a
pmc: PMC8341974
doi:
Types de publication
Journal Article
Langues
eng
Pagination
612-626Informations de copyright
This journal is © The Royal Society of Chemistry.
Déclaration de conflit d'intérêts
The authors declare no competing financial interest.
Références
Proc Natl Acad Sci U S A. 2019 Mar 19;116(12):5487-5492
pubmed: 30819897
Sci Rep. 2015 Feb 23;5:8529
pubmed: 25704306
Acta Crystallogr D Struct Biol. 2017 Feb 1;73(Pt 2):112-122
pubmed: 28177307
J Med Chem. 2019 Jun 27;62(12):5844-5862
pubmed: 31144814
Eur J Med Chem. 2018 Jul 15;155:806-823
pubmed: 29957526
J Biol Chem. 2016 Mar 25;291(13):7128-41
pubmed: 26861872
Front Pharmacol. 2012 May 03;3:82
pubmed: 22563317
Cell Metab. 2014 Apr 1;19(4):605-17
pubmed: 24703693
Biochemistry. 2007 Dec 18;46(50):14478-86
pubmed: 18027980
Acta Crystallogr D Biol Crystallogr. 2011 Apr;67(Pt 4):235-42
pubmed: 21460441
Neoplasia. 2018 Jul;20(7):745-756
pubmed: 29925042
J Biol Chem. 2007 Dec 21;282(51):37256-65
pubmed: 17951578
Nat Commun. 2015 Feb 12;6:6263
pubmed: 25672491
ACS Chem Biol. 2016 Oct 21;11(10):2685-2692
pubmed: 27459069
ACS Chem Biol. 2019 Sep 20;14(9):2014-2023
pubmed: 31433161
Acta Crystallogr D Biol Crystallogr. 2011 Apr;67(Pt 4):355-67
pubmed: 21460454
Angew Chem Int Ed Engl. 2017 Nov 20;56(47):14836-14841
pubmed: 29044784
Bioorg Chem. 2019 Jul;88:102941
pubmed: 31039470
Pharmacol Ther. 2018 Aug;188:140-154
pubmed: 29577959
Science. 2011 Nov 11;334(6057):806-9
pubmed: 22076378
Angew Chem Int Ed Engl. 2012 Apr 2;51(14):3423-7
pubmed: 22374802
Structure. 2014 Feb 4;22(2):345-52
pubmed: 24389023
ACS Med Chem Lett. 2020 Feb 06;11(10):1886-1892
pubmed: 33062169
Bioorg Med Chem Lett. 2016 Mar 15;26(6):1612-1617
pubmed: 26874402
Acta Crystallogr D Biol Crystallogr. 2010 Jan;66(Pt 1):12-21
pubmed: 20057044
Bioorg Med Chem Lett. 2019 Feb 1;29(3):461-465
pubmed: 30578034
Angew Chem Int Ed Engl. 2012 Sep 3;51(36):9083-7
pubmed: 22890609
ChemMedChem. 2014 Mar;9(3):434-7
pubmed: 24375937
Nat Protoc. 2014 Sep;9(9):2100-22
pubmed: 25101824
Nat Rev Drug Discov. 2016 Feb;15(2):87-95
pubmed: 26678621
J Struct Biol. 2013 May;182(2):136-43
pubmed: 23454361
J Med Chem. 2016 Feb 11;59(3):1021-31
pubmed: 26788965
Nat Struct Biol. 2001 Jul;8(7):621-5
pubmed: 11427894
Science. 2007 Jul 27;317(5837):516-9
pubmed: 17588900
ChemMedChem. 2018 Sep 19;13(18):1890-1894
pubmed: 30058233
Sci Rep. 2016 Mar 04;6:22643
pubmed: 26940860
Arch Biochem Biophys. 1979 Nov;198(1):78-88
pubmed: 507850
Biochemistry. 2015 May 19;54(19):3037-3050
pubmed: 25897714
Mol Cell Biol. 2003 May;23(9):3173-85
pubmed: 12697818
Curr Drug Targets. 2013 Jun 1;14(6):644-7
pubmed: 23410123
Science. 2013 Jul 5;341(6141):84-7
pubmed: 23828940
Cell. 2014 Dec 18;159(7):1615-25
pubmed: 25525879
J Med Chem. 2012 Jun 14;55(11):5582-90
pubmed: 22583019
J Biol Chem. 2012 Aug 17;287(34):28307-14
pubmed: 22767592
Cell Chem Biol. 2018 Jul 19;25(7):849-856.e8
pubmed: 29731425
Bioorg Med Chem. 2019 May 1;27(9):1767-1775
pubmed: 30885568
Nat Commun. 2018 Aug 28;9(1):3374
pubmed: 30154464
ChemMedChem. 2019 Apr 3;14(7):744-748
pubmed: 30734528
J Med Chem. 2017 Mar 23;60(6):2344-2360
pubmed: 28240897
ACS Chem Biol. 2018 Mar 16;13(3):685-693
pubmed: 29336543
J Biol Chem. 2013 Oct 25;288(43):31350-6
pubmed: 24052263
J Am Chem Soc. 2016 Sep 28;138(38):12304-7
pubmed: 27610633
Mol Cell. 2003 Feb;11(2):437-44
pubmed: 12620231
Cell Death Dis. 2018 Dec 18;10(1):9
pubmed: 30584257
Cell Chem Biol. 2017 Mar 16;24(3):339-345
pubmed: 28286128
J Neurosci. 2007 Mar 7;27(10):2606-16
pubmed: 17344398
J Med Chem. 2019 Apr 25;62(8):4131-4141
pubmed: 30986062
J Mol Graph Model. 2019 Jun;89:60-73
pubmed: 30870650
Acta Crystallogr F Struct Biol Commun. 2015 Dec;71(Pt 12):1498-510
pubmed: 26625292
J Med Chem. 2012 Jun 28;55(12):5760-73
pubmed: 22642300
Acta Crystallogr D Biol Crystallogr. 2010 Apr;66(Pt 4):486-501
pubmed: 20383002
Cell Metab. 2020 Sep 1;32(3):420-436.e12
pubmed: 32768387
Chem Sci. 2017 Sep 1;8(9):6400-6408
pubmed: 28989670
Cancer Cell. 2008 May;13(5):454-63
pubmed: 18455128
Biochemistry. 2006 Jan 10;45(1):272-82
pubmed: 16388603
Medchemcomm. 2018 Dec 7;10(1):164-168
pubmed: 30774863
J Cell Sci. 2016 Aug 1;129(15):2972-82
pubmed: 27311481
Prog Mol Biol Transl Sci. 2018;154:25-69
pubmed: 29413177
Appl Environ Microbiol. 2006 Dec;72(12):7468-76
pubmed: 16997975
Science. 2013 Mar 8;339(6124):1216-9
pubmed: 23471411
Annu Rev Biochem. 2016 Jun 2;85:405-29
pubmed: 27088879
Acta Crystallogr D Biol Crystallogr. 2010 Feb;66(Pt 2):125-32
pubmed: 20124692
J Biol Chem. 2016 Jul 8;291(28):14677-94
pubmed: 27226597
Cancer Cell. 2016 Mar 14;29(3):297-310
pubmed: 26977881
Nat Rev Cancer. 2015 Oct;15(10):608-24
pubmed: 26383140
Nature. 2013 Apr 4;496(7443):110-3
pubmed: 23552949
J Med Chem. 2019 Jun 13;62(11):5434-5452
pubmed: 31117516
J Biol Chem. 1990 Oct 5;265(28):17174-9
pubmed: 2211619
J Med Chem. 2019 Sep 12;62(17):8028-8052
pubmed: 31411465
Org Biomol Chem. 2016 Feb 21;14(7):2186-90
pubmed: 26796034
J Am Chem Soc. 2012 Mar 21;134(11):5138-48
pubmed: 22352831
Cell Res. 2017 Jul;27(7):898-915
pubmed: 28497810
J Med Chem. 2017 Mar 9;60(5):1928-1945
pubmed: 28135086
ACS Chem Biol. 2019 Aug 16;14(8):1802-1810
pubmed: 31373792
J Med Chem. 2016 Feb 25;59(4):1599-612
pubmed: 26696402
J Cell Sci. 2013 Oct 1;126(Pt 19):4369-80
pubmed: 23886946
Trends Pharmacol Sci. 2015 Nov;36(11):756-768
pubmed: 26538315
Biochemistry. 2017 Sep 26;56(38):5134-5146
pubmed: 28858522
Philos Trans R Soc Lond B Biol Sci. 2018 Jun 5;373(1748):
pubmed: 29685974
Trends Pharmacol Sci. 2017 May;38(5):459-472
pubmed: 28389129
EMBO Mol Med. 2013 Mar;5(3):344-52
pubmed: 23417962
Hepatology. 2013 Jun;57(6):2287-98
pubmed: 23348706
Nat Commun. 2020 Mar 13;11(1):1392
pubmed: 32170178