Sirtuin 1 Inhibiting Thiocyanates (S1th)-A New Class of Isotype Selective Inhibitors of NAD+ Dependent Lysine Deacetylases

Sirtuin 1 (Sirt1) is a NAD dependent lysine deacetylase associated with the pathogenesis of various diseases including cancer. In many cancer types Sirt1 expression is increased and higher levels have been associated with metastasis and poor prognosis. However, it was also shown, that Sirt1 can have...

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Autores: Wössner, Nathalie|||0000-0002-4402-2442, Alhalabi, Zayan, González Miranda, Jessica|||0000-0001-7732-1564, Swyter, Sören, Gan, Jin, Schmidtkunz, Karin, Zhang, Lin|||0000-0003-1998-0611, Vaquero, Alejandro|||0000-0002-8735-4156, Ovaa, Huib, Einsle, Oliver|||0000-0001-8722-2893, Sippl, Wolfgang, Jung, Manfred
Formato: artículo
Fecha de publicación:2020
País:España
Recursos:Universitat Autònoma de Barcelona
Repositorio:Dipòsit Digital de Documents de la UAB
Idioma:inglés
OAI Identifier:oai:ddd.uab.cat:236429
Acesso em linha:https://ddd.uab.cat/record/236429
https://dx.doi.org/urn:doi:10.3389/fonc.2020.00657
Access Level:acceso abierto
Palavra-chave:DNA damage
H2AX
Histone
Lysine deacetylase
P53
Sirtuins
Thiocyanate
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spelling Sirtuin 1 Inhibiting Thiocyanates (S1th)-A New Class of Isotype Selective Inhibitors of NAD+ Dependent Lysine DeacetylasesWössner, Nathalie|||0000-0002-4402-2442Alhalabi, ZayanGonzález Miranda, Jessica|||0000-0001-7732-1564Swyter, SörenGan, JinSchmidtkunz, KarinZhang, Lin|||0000-0003-1998-0611Vaquero, Alejandro|||0000-0002-8735-4156Ovaa, HuibEinsle, Oliver|||0000-0001-8722-2893Sippl, WolfgangJung, ManfredDNA damageH2AXHistoneLysine deacetylaseP53SirtuinsThiocyanateSirtuin 1 (Sirt1) is a NAD dependent lysine deacetylase associated with the pathogenesis of various diseases including cancer. In many cancer types Sirt1 expression is increased and higher levels have been associated with metastasis and poor prognosis. However, it was also shown, that Sirt1 can have tumor suppressing properties and in some instances even a dual role for the same cancer type has been reported. Increased Sirt1 activity has been linked to extension of the life span of cells, respectively, organisms by promoting DNA repair processes and downregulation of tumor suppressor proteins. This may have the downside of enhancing tumor growth and metastasis. In mice embryonic fibroblasts depletion of Sirt1 was shown to decrease levels of the DNA damage sensor histone H2AX. Impairment of DNA repair mechanisms by Sirt1 can promote tumorigenesis but also lower chemoresistance toward DNA targeting therapies. Despite many biological studies, there is currently just one small molecule Sirt1 inhibitor in clinical trials. Selisistat (EX-527) reached phase III clinical trials for treatment of Huntington's Disease. New small molecule Sirt1 modulators are crucial for further investigation of the contradicting roles of Sirt1 in cancer. We tested a small library of commercially available compounds that were proposed by virtual screening and docking studies against Sirt1, 2 and 3. A thienopyrimidone featuring a phenyl thiocyanate moiety was found to selectively inhibit Sirt1 with an IC of 13 μM. Structural analogs lacking the thiocyanate function did not show inhibition of Sirt1 revealing this group as key for the selectivity and affinity toward Sirt1. Further analogs with higher solubility were identified through iterative docking studies and in vitro testing. The most active compounds (down to 5 μM IC) were further studied in cells. The ratio of phosphorylated γH2AX to unmodified H2AX is lower when Sirt1 is depleted or inhibited. Our new Sirtuin 1 inhibiting thiocyanates (S1th) lead to similarly lowered γH2AX/H2AX ratios in mouse embryonic fibroblasts as Sirt1 knockout and treatment with the reference inhibitor EX-527. In addition to that we were able to show antiproliferative activity, inhibition of migration and colony forming as well as hyperacetylation of Sirt1 targets p53 and H3 by the S1th in cervical cancer cells (HeLa). These results reveal thiocyanates as a promising new class of selective Sirt1 inhibitors.Universitat Autònoma de Barcelona 22020-01-0120202020-01-01Articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttps://ddd.uab.cat/record/236429https://dx.doi.org/urn:doi:10.3389/fonc.2020.00657reponame:Dipòsit Digital de Documents de la UABinstname:Universitat Autònoma de BarcelonaInglésengAgència de Gestió d'Ajuts Universitaris i de Recerca https://doi.org/10.13039/501100003030 2017/SGR-148Agencia Estatal de Investigación https://doi.org/10.13039/501100011033 SAF2017-88975-Ropen accesshttp://purl.org/coar/access_right/c_abf2Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.https://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:ddd.uab.cat:2364292026-06-06T12:50:31Z
dc.title.none.fl_str_mv Sirtuin 1 Inhibiting Thiocyanates (S1th)-A New Class of Isotype Selective Inhibitors of NAD+ Dependent Lysine Deacetylases
title Sirtuin 1 Inhibiting Thiocyanates (S1th)-A New Class of Isotype Selective Inhibitors of NAD+ Dependent Lysine Deacetylases
spellingShingle Sirtuin 1 Inhibiting Thiocyanates (S1th)-A New Class of Isotype Selective Inhibitors of NAD+ Dependent Lysine Deacetylases
Wössner, Nathalie|||0000-0002-4402-2442
DNA damage
H2AX
Histone
Lysine deacetylase
P53
Sirtuins
Thiocyanate
title_short Sirtuin 1 Inhibiting Thiocyanates (S1th)-A New Class of Isotype Selective Inhibitors of NAD+ Dependent Lysine Deacetylases
title_full Sirtuin 1 Inhibiting Thiocyanates (S1th)-A New Class of Isotype Selective Inhibitors of NAD+ Dependent Lysine Deacetylases
title_fullStr Sirtuin 1 Inhibiting Thiocyanates (S1th)-A New Class of Isotype Selective Inhibitors of NAD+ Dependent Lysine Deacetylases
title_full_unstemmed Sirtuin 1 Inhibiting Thiocyanates (S1th)-A New Class of Isotype Selective Inhibitors of NAD+ Dependent Lysine Deacetylases
title_sort Sirtuin 1 Inhibiting Thiocyanates (S1th)-A New Class of Isotype Selective Inhibitors of NAD+ Dependent Lysine Deacetylases
dc.creator.none.fl_str_mv Wössner, Nathalie|||0000-0002-4402-2442
Alhalabi, Zayan
González Miranda, Jessica|||0000-0001-7732-1564
Swyter, Sören
Gan, Jin
Schmidtkunz, Karin
Zhang, Lin|||0000-0003-1998-0611
Vaquero, Alejandro|||0000-0002-8735-4156
Ovaa, Huib
Einsle, Oliver|||0000-0001-8722-2893
Sippl, Wolfgang
Jung, Manfred
author Wössner, Nathalie|||0000-0002-4402-2442
author_facet Wössner, Nathalie|||0000-0002-4402-2442
Alhalabi, Zayan
González Miranda, Jessica|||0000-0001-7732-1564
Swyter, Sören
Gan, Jin
Schmidtkunz, Karin
Zhang, Lin|||0000-0003-1998-0611
Vaquero, Alejandro|||0000-0002-8735-4156
Ovaa, Huib
Einsle, Oliver|||0000-0001-8722-2893
Sippl, Wolfgang
Jung, Manfred
author_role author
author2 Alhalabi, Zayan
González Miranda, Jessica|||0000-0001-7732-1564
Swyter, Sören
Gan, Jin
Schmidtkunz, Karin
Zhang, Lin|||0000-0003-1998-0611
Vaquero, Alejandro|||0000-0002-8735-4156
Ovaa, Huib
Einsle, Oliver|||0000-0001-8722-2893
Sippl, Wolfgang
Jung, Manfred
author2_role author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Universitat Autònoma de Barcelona
dc.subject.none.fl_str_mv DNA damage
H2AX
Histone
Lysine deacetylase
P53
Sirtuins
Thiocyanate
topic DNA damage
H2AX
Histone
Lysine deacetylase
P53
Sirtuins
Thiocyanate
description Sirtuin 1 (Sirt1) is a NAD dependent lysine deacetylase associated with the pathogenesis of various diseases including cancer. In many cancer types Sirt1 expression is increased and higher levels have been associated with metastasis and poor prognosis. However, it was also shown, that Sirt1 can have tumor suppressing properties and in some instances even a dual role for the same cancer type has been reported. Increased Sirt1 activity has been linked to extension of the life span of cells, respectively, organisms by promoting DNA repair processes and downregulation of tumor suppressor proteins. This may have the downside of enhancing tumor growth and metastasis. In mice embryonic fibroblasts depletion of Sirt1 was shown to decrease levels of the DNA damage sensor histone H2AX. Impairment of DNA repair mechanisms by Sirt1 can promote tumorigenesis but also lower chemoresistance toward DNA targeting therapies. Despite many biological studies, there is currently just one small molecule Sirt1 inhibitor in clinical trials. Selisistat (EX-527) reached phase III clinical trials for treatment of Huntington's Disease. New small molecule Sirt1 modulators are crucial for further investigation of the contradicting roles of Sirt1 in cancer. We tested a small library of commercially available compounds that were proposed by virtual screening and docking studies against Sirt1, 2 and 3. A thienopyrimidone featuring a phenyl thiocyanate moiety was found to selectively inhibit Sirt1 with an IC of 13 μM. Structural analogs lacking the thiocyanate function did not show inhibition of Sirt1 revealing this group as key for the selectivity and affinity toward Sirt1. Further analogs with higher solubility were identified through iterative docking studies and in vitro testing. The most active compounds (down to 5 μM IC) were further studied in cells. The ratio of phosphorylated γH2AX to unmodified H2AX is lower when Sirt1 is depleted or inhibited. Our new Sirtuin 1 inhibiting thiocyanates (S1th) lead to similarly lowered γH2AX/H2AX ratios in mouse embryonic fibroblasts as Sirt1 knockout and treatment with the reference inhibitor EX-527. In addition to that we were able to show antiproliferative activity, inhibition of migration and colony forming as well as hyperacetylation of Sirt1 targets p53 and H3 by the S1th in cervical cancer cells (HeLa). These results reveal thiocyanates as a promising new class of selective Sirt1 inhibitors.
publishDate 2020
dc.date.none.fl_str_mv 2
2020-01-01
2020
2020-01-01
dc.type.none.fl_str_mv Article
http://purl.org/coar/resource_type/c_6501
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://ddd.uab.cat/record/236429
https://dx.doi.org/urn:doi:10.3389/fonc.2020.00657
url https://ddd.uab.cat/record/236429
https://dx.doi.org/urn:doi:10.3389/fonc.2020.00657
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.relation.none.fl_str_mv Agència de Gestió d'Ajuts Universitaris i de Recerca https://doi.org/10.13039/501100003030 2017/SGR-148
Agencia Estatal de Investigación https://doi.org/10.13039/501100011033 SAF2017-88975-R
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
https://creativecommons.org/licenses/by/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
https://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.source.none.fl_str_mv reponame:Dipòsit Digital de Documents de la UAB
instname:Universitat Autònoma de Barcelona
instname_str Universitat Autònoma de Barcelona
reponame_str Dipòsit Digital de Documents de la UAB
collection Dipòsit Digital de Documents de la UAB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,301603

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