Multicomponent Synthesis, Binding Mode, and Structure-Activity Relationship of Selective Histone Deacetylase 6 (HDAC6) Inhibitors with Bifurcated Capping Groups.

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Abstrakt

Tytuł:: Multicomponent Synthesis, Binding Mode, and Structure-Activity Relationship of Selective Histone Deacetylase 6 (HDAC6) Inhibitors with Bifurcated Capping Groups.
Autorzy:: Reßing N; Institute for Drug Discovery, Medical Faculty, Leipzig University, Brüderstr. 34, 04103 Leipzig, Germany.; Pharmaceutical and Cell Biological Chemistry, Pharmaceutical Institute, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany.
Sönnichsen M; Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Heinrich Heine University Düsseldorf, Moorenstr. 5, 40225 Düsseldorf, Germany.
Osko JD; Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, 231 South 34th Street, Philadelphia, Pennsylvania 19104-6323, United States.
Schöler A; Institute for Drug Discovery, Medical Faculty, Leipzig University, Brüderstr. 34, 04103 Leipzig, Germany.
Schliehe-Diecks J; Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Heinrich Heine University Düsseldorf, Moorenstr. 5, 40225 Düsseldorf, Germany.
Skerhut A; Institute for Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Universitätsstraße 1, 40225 Düsseldorf, Germany.
Borkhardt A; Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Heinrich Heine University Düsseldorf, Moorenstr. 5, 40225 Düsseldorf, Germany.
Hauer J; Department of Pediatrics, Pediatric Hematology and Oncology, University Hospital Carl Gustav Carus, Dresden University of Technology, Fetscherstr. 74, 01307 Dresden, Germany.
Kassack MU; Institute for Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Universitätsstraße 1, 40225 Düsseldorf, Germany.
Christianson DW; Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, 231 South 34th Street, Philadelphia, Pennsylvania 19104-6323, United States.
Bhatia S; Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Heinrich Heine University Düsseldorf, Moorenstr. 5, 40225 Düsseldorf, Germany.
Hansen FK; Institute for Drug Discovery, Medical Faculty, Leipzig University, Brüderstr. 34, 04103 Leipzig, Germany.; Pharmaceutical and Cell Biological Chemistry, Pharmaceutical Institute, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany.
Źródło:: Journal of medicinal chemistry [J Med Chem] 2020 Sep 24; Vol. 63 (18), pp. 10339-10351. Date of Electronic Publication: 2020 Sep 01.
Typ publikacji:: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
Język:: English
Imprint Name(s):: Publication: Washington Dc : American Chemical Society
Original Publication: [Easton, Pa.] : American Chemical Society, [c1963-
MeSH Terms:: Histone Deacetylase 6/*antagonists & inhibitors
Histone Deacetylase Inhibitors/*pharmacology
Tetrazoles/*pharmacology
Animals ; Antineoplastic Agents/chemical synthesis ; Antineoplastic Agents/metabolism ; Antineoplastic Agents/pharmacology ; Bortezomib/pharmacology ; Cell Line, Tumor ; Daunorubicin/pharmacology ; Drug Screening Assays, Antitumor ; Drug Synergism ; Epirubicin/pharmacology ; Histone Deacetylase 6/metabolism ; Histone Deacetylase Inhibitors/chemical synthesis ; Histone Deacetylase Inhibitors/metabolism ; Humans ; Microsomes, Liver/metabolism ; Molecular Structure ; Protein Binding ; Structure-Activity Relationship ; Tetrazoles/chemical synthesis ; Tetrazoles/metabolism
References:: J Med Chem. 2013 Aug 22;56(16):6297-313. (PMID: 23627282)
ChemMedChem. 2019 May 6;14(9):912-926. (PMID: 30664827)
Eur J Med Chem. 2016 Oct 4;121:451-483. (PMID: 27318122)
Sci Transl Med. 2019 Sep 11;11(509):. (PMID: 31511426)
Angew Chem Int Ed Engl. 2012 Aug 27;51(35):8708-20. (PMID: 22711561)
Nat Commun. 2017 May 18;8:15368. (PMID: 28516954)
Expert Opin Ther Pat. 2020 Feb;30(2):121-136. (PMID: 31865813)
Eur J Med Chem. 2018 Oct 5;158:801-813. (PMID: 30245402)
J Med Chem. 2018 Sep 13;61(17):8054-8060. (PMID: 30118224)
Clin Epigenetics. 2018 Dec 29;10(1):162. (PMID: 30594243)
J Cell Sci. 2009 Oct 1;122(Pt 19):3531-41. (PMID: 19737819)
J Med Chem. 2020 Jan 9;63(1):23-39. (PMID: 31415174)
Int J Mol Sci. 2017 Jul 01;18(7):. (PMID: 28671573)
Chem Commun (Camb). 2016 Feb 21;52(15):3219-22. (PMID: 26810607)
Cold Spring Harb Perspect Med. 2016 Oct 3;6(10):. (PMID: 27599530)
Acta Crystallogr D Biol Crystallogr. 2011 Apr;67(Pt 4):235-42. (PMID: 21460441)
J Med Chem. 2010 Apr 8;53(7):2719-40. (PMID: 20131845)
Angew Chem Int Ed Engl. 2005 May 20;44(21):3186-216. (PMID: 15898057)
Proc Natl Acad Sci U S A. 2009 May 12;106(19):7751-5. (PMID: 19416910)
Eur J Med Chem. 2010 Jun;45(6):2095-116. (PMID: 20223566)
CA Cancer J Clin. 2013 Nov-Dec;63(6):419-37. (PMID: 24590861)
Pediatr Blood Cancer. 2010 Aug;55(2):254-9. (PMID: 20582937)
Int J Cancer. 2019 Aug 1;145(3):735-747. (PMID: 30694564)
Biochemistry. 2018 Jul 3;57(26):3916-3924. (PMID: 29775292)
Acta Crystallogr D Biol Crystallogr. 2010 Jan;66(Pt 1):12-21. (PMID: 20057044)
Chemistry. 2014 Aug 25;20(35):11058-68. (PMID: 25044441)
Nat Chem Biol. 2016 Sep;12(9):741-7. (PMID: 27454933)
Proc Natl Acad Sci U S A. 2017 Dec 19;114(51):13459-13464. (PMID: 29203661)
Bioorg Med Chem. 2019 Oct 1;27(19):115039. (PMID: 31420257)
Methods Enzymol. 2019;626:447-474. (PMID: 31606087)
Acta Crystallogr D Biol Crystallogr. 2010 Apr;66(Pt 4):486-501. (PMID: 20383002)
Cardiology. 2010;115(2):155-62. (PMID: 20016174)
ChemMedChem. 2016 Jan 5;11(1):81-92. (PMID: 26592932)
Anal Biochem. 2003 Aug 1;319(1):42-8. (PMID: 12842105)
Front Oncol. 2018 Mar 29;8:92. (PMID: 29651407)
Acta Crystallogr D Biol Crystallogr. 2010 Feb;66(Pt 2):213-21. (PMID: 20124702)
Mol Cell Biol. 2008 Mar;28(5):1688-701. (PMID: 18180281)
Org Lett. 2018 Jun 1;20(11):3255-3258. (PMID: 29790770)
Trends Cell Biol. 2008 Jun;18(6):291-7. (PMID: 18472263)
Acta Crystallogr D Biol Crystallogr. 2011 Apr;67(Pt 4):271-81. (PMID: 21460445)
Mol Cancer Ther. 2011 Nov;10(11):2034-42. (PMID: 22072815)
Pharmaceuticals (Basel). 2010 Aug 26;3(9):2751-2767. (PMID: 27713375)
Blood. 2012 Jul 12;120(2):285-90. (PMID: 22653976)
J Med Chem. 2018 Nov 21;61(22):10299-10309. (PMID: 30365892)
Mol Neurodegener. 2013 Jan 29;8:7. (PMID: 23356410)
Grant Information:: P30 GM124165 United States GM NIGMS NIH HHS; R01 GM049758 United States GM NIGMS NIH HHS; S10 RR029205 United States RR NCRR NIH HHS
Substance Nomenclature:: 0 (Antineoplastic Agents)
0 (Histone Deacetylase Inhibitors)
0 (Tetrazoles)
3Z8479ZZ5X (Epirubicin)
69G8BD63PP (Bortezomib)
EC 3.5.1.98 (HDAC6 protein, human)
EC 3.5.1.98 (Hdac6 protein, mouse)
EC 3.5.1.98 (Histone Deacetylase 6)
ZS7284E0ZP (Daunorubicin)
Entry Date(s):: Date Created: 20200818 Date Completed: 20210104 Latest Revision: 20210925
Update Code:: 20240105
PubMed Central ID:: PMC7762828
DOI:: 10.1021/acs.jmedchem.9b01888
PMID:: 32803970
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Histone deacetylase 6 (HDAC6) is an emerging target for the treatment of cancer, neurodegenerative diseases, inflammation, and other diseases. Here, we present the multicomponent synthesis and structure-activity relationship of a series of tetrazole-based HDAC6 inhibitors. We discovered the hit compound NR-160 by investigating the inhibition of recombinant HDAC enzymes and protein acetylation. A cocrystal structure of HDAC6 complexed with NR-160 disclosed that the steric complementarity of the bifurcated capping group of NR-160 to the L1 and L2 loop pockets may be responsible for its HDAC6-selective inhibition. While NR-160 displayed only low cytotoxicity as a single agent against leukemia cell lines, it augmented the apoptosis induction of the proteasome inhibitor bortezomib in combination experiments significantly. Furthermore, a combinatorial high-throughput drug screen revealed significantly enhanced cytotoxicity when NR-160 was used in combination with epirubicin and daunorubicin. The synergistic effect in combination with bortezomib and anthracyclines highlights the potential of NR-160 in combination therapies.

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