Sirtuin 1 Inhibiting Thiocyanates (S1th)-A New Class of Isotype Selective Inhibitors of NAD+ Dependent Lysine Deacetylases
Wössner, Nathalie (Institute of Pharmaceutical Sciences. University of Freiburg. Department of Pharmaceutical and Medicinal Chemistry)
Alhalabi, Zayan (Institute of Pharmacy. University of Halle-Wittenberg. Department of Medicinal Chemistry)
González Miranda, Jessica (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Swyter, Sören (Institute of Pharmaceutical Sciences. University of Freiburg)
Gan, Jin (Oncode Institute, Leiden University Medical Center, Leiden)
Schmidtkunz, Karin (Department of Pharmaceutical and Medicinal Chemistry. Institute of Pharmaceutical Sciences. University of Freiburg)
Zhang, Lin (Department of Protein Crystallography. Institute of Biochemistry. University of Freiburg)
Vaquero, Alejandro (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Ovaa, Huib (Oncode Institute. Leiden University Medical Center)
Einsle, Oliver (Department of Protein Crystallography. Institute of Biochemistry. University of Freiburg)
Sippl, Wolfgang (Department of Medicinal Chemistry. Institute of Pharmacy. University of Halle-Wittenberg)
Jung, Manfred (Department of Pharmaceutical and Medicinal Chemistry. Institute of Pharmaceutical Sciences. University of Freiburg)
Universitat Autònoma de Barcelona

Date:	2020
Abstract:	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.
Grants:	Agència de Gestió d'Ajuts Universitaris i de Recerca 2017-SGR148 Ministerio de Economía y Competitividad SAF2017-88975-R
Note:	Altres ajuts: MJ, WS, and NW thank the Josep Carreras Foundation for institutional support.
Rights:	Aquest 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.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	DNA damage ; H2AX ; Histone ; Lysine deacetylase ; P53 ; Sirtuins ; Thiocyanate
Published in:	Frontiers in Oncology, Vol. 10 (30 2020) , p. 657, ISSN 2234-943X

DOI: 10.3389/fonc.2020.00657
PMID: 32426286

15 p, 1.5 MB

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Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut d'Investigació en Ciencies de la Salut Germans Trias i Pujol (IGTP) > Josep Carreras Leukaemia Research Institute
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