Design and Synthesis of Dihydroxamic Acids as HDAC6/8/10 Inhibitors.
Cell Proliferation
/ drug effects
Cell Survival
/ drug effects
Dose-Response Relationship, Drug
Drug Design
Histone Deacetylase 6
/ antagonists & inhibitors
Histone Deacetylase Inhibitors
/ chemical synthesis
Histone Deacetylases
/ metabolism
Humans
Hydroxamic Acids
/ chemical synthesis
Molecular Structure
Repressor Proteins
/ antagonists & inhibitors
Structure-Activity Relationship
Tumor Cells, Cultured
HDAC10
HDAC8
inhibitors
polypharmacology
targeted therapy
Journal
ChemMedChem
ISSN: 1860-7187
Titre abrégé: ChemMedChem
Pays: Germany
ID NLM: 101259013
Informations de publication
Date de publication:
03 07 2020
03 07 2020
Historique:
received:
06
03
2020
revised:
23
04
2020
pubmed:
30
4
2020
medline:
16
6
2021
entrez:
30
4
2020
Statut:
ppublish
Résumé
We report the synthesis and evaluation of a class of selective multitarget agents for the inhibition of HDAC6, HDAC8, and HDAC10. The concept for this study grew out of a structural analysis of the two selective inhibitors Tubastatin A (HDAC6/10) and PCI-34051 (HDAC8), which we recognized share the same N-benzylindole core. Hybridization of the two inhibitor structures resulted in dihydroxamic acids with benzyl-indole and -indazole core motifs. These substances exhibit potent activity against HDAC6, HDAC8, and HDAC10, while retaining selectivity over HDAC1, HDAC2, and HDAC3. The best substance inhibited the viability of the SK-N-BE(2)C neuroblastoma cell line with an IC
Identifiants
pubmed: 32348628
doi: 10.1002/cmdc.202000149
pmc: PMC7335359
mid: NIHMS1590164
doi:
Substances chimiques
Histone Deacetylase Inhibitors
0
Hydroxamic Acids
0
Repressor Proteins
0
HDAC6 protein, human
EC 3.5.1.98
HDAC8 protein, human
EC 3.5.1.98
Histone Deacetylase 6
EC 3.5.1.98
Histone Deacetylases
EC 3.5.1.98
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
1163-1174Subventions
Organisme : NIGMS NIH HHS
ID : R01 GM049758
Pays : United States
Informations de copyright
© 2020 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.
Références
ChemMedChem. 2016 Jun 20;11(12):1227-41
pubmed: 26891251
Cell Death Dis. 2015 Feb 19;6:e1657
pubmed: 25695609
Acta Crystallogr D Biol Crystallogr. 2010 Jan;66(Pt 1):12-21
pubmed: 20057044
Methods Enzymol. 2019;626:447-474
pubmed: 31606087
Nat Commun. 2017 May 18;8:15368
pubmed: 28516954
Bioorg Med Chem Lett. 2018 Aug 1;28(14):2493-2497
pubmed: 29871848
Bioorg Med Chem. 2010 Aug 15;18(16):5950-64
pubmed: 20650640
Nat Commun. 2015 Dec 03;6:10091
pubmed: 26631872
Bioorg Med Chem Lett. 2016 Jun 15;26(12):2931-2935
pubmed: 27142751
J Med Chem. 2018 Jul 26;61(14):6056-6074
pubmed: 29940115
Cold Spring Harb Perspect Med. 2016 Oct 3;6(10):
pubmed: 27599530
RSC Adv. 2018 Apr 9;8(24):13121-13128
pubmed: 35542511
Acta Crystallogr D Biol Crystallogr. 2011 Apr;67(Pt 4):235-42
pubmed: 21460441
Clin Cancer Res. 2009 Jan 1;15(1):91-9
pubmed: 19118036
J Med Chem. 2019 May 9;62(9):4426-4443
pubmed: 30964290
ChemMedChem. 2014 Mar;9(3):523-6
pubmed: 24730063
Arch Toxicol. 2018 Aug;92(8):2649-2664
pubmed: 29947893
Proc Natl Acad Sci U S A. 2013 Jul 9;110(28):E2592-601
pubmed: 23801752
Int J Cancer. 2019 Aug 1;145(3):735-747
pubmed: 30694564
Eur J Med Chem. 2017 Feb 15;127:115-127
pubmed: 28038324
Cancer Lett. 2009 May 8;277(1):8-21
pubmed: 18824292
Nat Chem Biol. 2016 Sep;12(9):741-7
pubmed: 27454933
ACS Med Chem Lett. 2018 Mar 26;9(4):312-317
pubmed: 29670692
Biochemistry. 2019 Dec 10;58(49):4957-4969
pubmed: 31746596
Eur J Med Chem. 2016 Oct 4;121:451-483
pubmed: 27318122
Clin Cancer Res. 2012 Aug 1;18(15):4104-13
pubmed: 22693356
Cancer Res. 2010 May 1;70(9):3647-56
pubmed: 20388807
Nature. 2012 Sep 13;489(7415):313-7
pubmed: 22885700
Eur J Med Chem. 2018 Jan 1;143:1277-1300
pubmed: 29126724
J Med Chem. 2016 Oct 13;59(19):8967-9004
pubmed: 27606546
Acta Crystallogr D Biol Crystallogr. 2010 Apr;66(Pt 4):486-501
pubmed: 20383002
ChemMedChem. 2019 Jun 5;14(11):1067-1073
pubmed: 30958639
Acta Crystallogr D Biol Crystallogr. 2010 Feb;66(Pt 2):213-21
pubmed: 20124702
Clin Transl Med. 2018 Jan 17;7(1):3
pubmed: 29340951
ChemMedChem. 2020 Jul 3;15(13):1163-1174
pubmed: 32348628
Acta Crystallogr D Biol Crystallogr. 2011 Apr;67(Pt 4):271-81
pubmed: 21460445
Sci Rep. 2018 Jul 3;8(1):10039
pubmed: 29968769
J Med Chem. 2014 Oct 9;57(19):7874-87
pubmed: 24946140
Acta Crystallogr D Biol Crystallogr. 2013 Jul;69(Pt 7):1204-14
pubmed: 23793146
J Appl Crystallogr. 2007 Aug 1;40(Pt 4):658-674
pubmed: 19461840
J Med Chem. 2019 Aug 8;62(15):7042-7057
pubmed: 31271281
J Med Chem. 2018 Nov 21;61(22):10299-10309
pubmed: 30365892
Clin Cancer Res. 2017 Jul 1;23(13):3307-3315
pubmed: 28053023
Protein Cell. 2019 Aug;10(8):606-609
pubmed: 30603959
J Med Chem. 2012 Feb 23;55(4):1465-77
pubmed: 22260166
Cell. 2010 Nov 24;143(5):737-49
pubmed: 21111234
Leukemia. 2008 May;22(5):1026-34
pubmed: 18256683
ChemMedChem. 2014 Mar;9(3):602-13
pubmed: 23956109