Combined Scaffold Evaluation and Systems-Level Transcriptome-Based Analysis for Accelerated Lead Optimization Reveals Ribosomal Targeting Spirooxindole Cyclopropanes.
Antineoplastic Agents
/ chemical synthesis
Cell Proliferation
/ drug effects
Cyclopropanes
/ chemical synthesis
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Humans
Molecular Structure
Oxindoles
/ chemical synthesis
RNA, Neoplasm
/ drug effects
Ribosomes
/ drug effects
Spiro Compounds
/ chemical synthesis
Structure-Activity Relationship
Transcriptome
Tumor Cells, Cultured
drug discovery
mechanism of action
natural products
spirooxindoles
transcriptome network
Journal
ChemMedChem
ISSN: 1860-7187
Titre abrégé: ChemMedChem
Pays: Germany
ID NLM: 101259013
Informations de publication
Date de publication:
18 09 2019
18 09 2019
Historique:
received:
02
05
2019
pubmed:
30
5
2019
medline:
23
9
2020
entrez:
30
5
2019
Statut:
ppublish
Résumé
With evolutionary drug resistance impacting efforts to treat disease, the need for small molecules that exhibit novel molecular mechanisms of action is paramount. In this study, we combined scaffold-directed synthesis with a hybrid experimental and transcriptome analysis to identify bis-spirooxindole cyclopropanes that inhibit cancer cell proliferation through disruption of ribosomal function. These findings demonstrate the value of an integrated, biologically inspired synthesis and assay strategy for the accelerated identification of first-in-class cancer therapeutic candidates.
Identifiants
pubmed: 31140738
doi: 10.1002/cmdc.201900266
pmc: PMC6750968
mid: NIHMS1048926
doi:
Substances chimiques
Antineoplastic Agents
0
Cyclopropanes
0
Oxindoles
0
RNA, Neoplasm
0
Spiro Compounds
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1653-1661Subventions
Organisme : Walther Cancer Foundation
ID : ENSCCII Training Grant
Pays : International
Organisme : Walther Cancer Foundation
ID : Advancing Basic Cancer Research Program
Pays : International
Organisme : NIH HHS
ID : Chemistry, Biochemistry, Biology Training Grant
Pays : United States
Organisme : NIH HHS
ID : 1F32CA210583
Pays : United States
Organisme : American Cancer Society Institutional Research Grant
ID : IRG-14-195-01
Pays : International
Organisme : NCI NIH HHS
ID : F32 CA210583
Pays : United States
Organisme : National Science Foundation
ID : CHE-1056242 and CHE-1665440
Pays : International
Organisme : Indiana Clinical and Translational Sciences Institute
ID : TL1R001107
Pays : International
Informations de copyright
© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.
Références
Annu Rev Pharmacol Toxicol. 2000;40:193-207
pubmed: 10836133
Angew Chem Int Ed Engl. 2001 Sep 17;40(18):3341-3350
pubmed: 11592134
Methods Mol Med. 2005;110:39-48
pubmed: 15901925
Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50
pubmed: 16199517
J Nat Prod. 2006 Jan;69(1):14-7
pubmed: 16441060
Bioorg Med Chem Lett. 2006 Apr 15;16(8):2109-12
pubmed: 16464578
Bioorg Med Chem Lett. 2006 Apr 15;16(8):2105-8
pubmed: 16480865
NeuroRx. 2005 Oct;2(4):541-53
pubmed: 16489364
Bioorg Med Chem. 2006 Sep 15;14(18):6434-43
pubmed: 16759872
Biophys J. 2006 Dec 1;91(11):4258-72
pubmed: 16980368
Nat Protoc. 2006;1(3):1112-6
pubmed: 17406391
Bioorg Med Chem Lett. 2007 Nov 15;17(22):6270-3
pubmed: 17911024
Nat Biotechnol. 2007 Oct;25(10):1119-26
pubmed: 17921997
Angew Chem Int Ed Engl. 2007;46(46):8748-58
pubmed: 17943924
J Nat Prod. 2008 Mar;71(3):464-8
pubmed: 18257534
Curr Opin Chem Biol. 2008 Jun;12(3):318-23
pubmed: 18435937
Nat Chem Biol. 2009 Jul;5(7):479-83
pubmed: 19483698
J Biomol Screen. 2009 Jul;14(6):690-9
pubmed: 19531667
Nat Rev Drug Discov. 2009 Jul;8(7):541-6
pubmed: 19543224
J Am Chem Soc. 2009 Sep 16;131(36):13099-106
pubmed: 19691345
J Med Chem. 2010 Jul 22;53(14):5155-64
pubmed: 20568778
Nat Chem. 2010 Sep;2(9):735-40
pubmed: 20729892
Nat Rev Drug Discov. 2011 Jun 24;10(7):507-19
pubmed: 21701501
Nat Prod Rep. 2011 Sep;28(9):1483-92
pubmed: 21779594
Org Biomol Chem. 2011 Sep 21;9(18):6196-9
pubmed: 21796319
Angew Chem Int Ed Engl. 2011 Nov 11;50(46):10800-26
pubmed: 22038946
Nat Rev Drug Discov. 2012 Mar 01;11(3):191-200
pubmed: 22378269
Nat Protoc. 2012 Mar 01;7(3):562-78
pubmed: 22383036
Mol Oncol. 2012 Apr;6(2):155-76
pubmed: 22440008
Org Lett. 2012 May 4;14(9):2270-3
pubmed: 22524490
Org Biomol Chem. 2012 Jul 21;10(27):5165-81
pubmed: 22581310
Chemistry. 2012 Jul 27;18(31):9645-50
pubmed: 22815218
Cell Mol Neurobiol. 2013 Jan;33(1):129-35
pubmed: 22968712
Nat Biotechnol. 2013 Jan;31(1):46-53
pubmed: 23222703
Nat Protoc. 2014 Jan;9(1):171-81
pubmed: 24385147
Eur J Med Chem. 2014 May 22;79:266-72
pubmed: 24747063
J Med Chem. 2015 Jan 8;58(1):130-46
pubmed: 24867403
Org Lett. 2014 Jun 20;16(12):3192-5
pubmed: 24912009
Drug Discov Today Technol. 2004 Dec;1(4):337-41
pubmed: 24981612
Eur J Med Chem. 2015 Jun 5;97:673-98
pubmed: 24994707
Nat Rev Drug Discov. 2014 Aug;13(8):588-602
pubmed: 25033736
J Org Chem. 2014 Nov 7;79(21):10709-15
pubmed: 25333339
Nucleic Acids Res. 2015 Jan;43(Database issue):D447-52
pubmed: 25352553
Nat Rev Drug Discov. 2015 Feb;14(2):111-29
pubmed: 25614221
Nat Rev Drug Discov. 2015 Apr;14(4):261-78
pubmed: 25743081
Biomed Res Int. 2015;2015:239654
pubmed: 26060814
Cell. 2015 Jul 16;162(2):441-451
pubmed: 26186195
Bioorg Med Chem Lett. 2015 Oct 15;25(20):4580-6
pubmed: 26330077
Mol Divers. 2016 Feb;20(1):299-344
pubmed: 26419598
Nat Rev Drug Discov. 2016 Mar;15(3):204-16
pubmed: 26669673
ACS Infect Dis. 2016 Jun 10;2(6):382-92
pubmed: 27627626