SIRT6 inhibitors with salicylate-like structure show immunosuppressive and chemosensitizing effects

Patrizia Damonte; Giovanna Sociali; Marco Daniele Parenti; Debora Soncini; Inga Bauer; Silvia Boero; Alessia Grozio; Maria von Holtey; Francesco Piacente; Pamela Becherini; Roberta Sanguineti; Annalisa Salis; Gianluca Damonte; Michele Cea; Maximilien Murone; Alessandro Poggi; Alessio Nencioni; Alberto Del Rio; Santina Bruzzone

doi:10.1016/j.bmc.2017.09.023

SIRT6 inhibitors with salicylate-like structure show immunosuppressive and chemosensitizing effects

Bioorg Med Chem. 2017 Oct 15;25(20):5849-5858. doi: 10.1016/j.bmc.2017.09.023. Epub 2017 Sep 19.

Authors

Patrizia Damonte¹, Giovanna Sociali², Marco Daniele Parenti³, Debora Soncini¹, Inga Bauer¹, Silvia Boero⁴, Alessia Grozio², Maria von Holtey⁵, Francesco Piacente¹, Pamela Becherini¹, Roberta Sanguineti¹, Annalisa Salis⁶, Gianluca Damonte⁷, Michele Cea¹, Maximilien Murone⁸, Alessandro Poggi⁹, Alessio Nencioni¹⁰, Alberto Del Rio¹¹, Santina Bruzzone¹²

Affiliations

¹ Department of Internal Medicine, University of Genoa, V.le Benedetto XV 6, 16132 Genoa, Italy.
² Department of Experimental Medicine, Section of Biochemistry, University of Genoa, V.le Benedetto XV 1, 16132 Genoa, Italy.
³ Institute of Organic Synthesis and Photoreactivity (ISOF), National Research Council (CNR), Via P. Gobetti 101, 40129 Bologna, Italy.
⁴ Department of Internal Medicine, University of Genoa, V.le Benedetto XV 6, 16132 Genoa, Italy; IRCCS Azienda Ospedaliera Universitaria San Martino-IST, Istituto Nazionale per la Ricerca sul Cancro, 16132 Genoa, Italy.
⁵ Debiopharm International S.A., Chemin Messidor 5-7, 1002 Lausanne, Switzerland; Roche Diagnostics International AG, Forrenstrasse 2, 6343 Rotkreuz, Switzerland.
⁶ CEBR, University of Genova, V.le Benedetto XV, 7, 16132 Genoa, Italy.
⁷ Department of Experimental Medicine, Section of Biochemistry, University of Genoa, V.le Benedetto XV 1, 16132 Genoa, Italy; CEBR, University of Genova, V.le Benedetto XV, 7, 16132 Genoa, Italy.
⁸ Debiopharm International S.A., Chemin Messidor 5-7, 1002 Lausanne, Switzerland; Cellestia Biotech AG, Hochbergerstrasse 60C, 4057 Basel, Switzerland.
⁹ IRCCS Azienda Ospedaliera Universitaria San Martino-IST, Istituto Nazionale per la Ricerca sul Cancro, 16132 Genoa, Italy.
¹⁰ Department of Internal Medicine, University of Genoa, V.le Benedetto XV 6, 16132 Genoa, Italy; IRCCS Azienda Ospedaliera Universitaria San Martino-IST, Istituto Nazionale per la Ricerca sul Cancro, 16132 Genoa, Italy. Electronic address: [email protected].
¹¹ Institute of Organic Synthesis and Photoreactivity (ISOF), National Research Council (CNR), Via P. Gobetti 101, 40129 Bologna, Italy; Innovamol Srls, Viale A. Corassori 24, 41124 Modena, Italy. Electronic address: [email protected].
¹² Department of Experimental Medicine, Section of Biochemistry, University of Genoa, V.le Benedetto XV 1, 16132 Genoa, Italy; CEBR, University of Genova, V.le Benedetto XV, 7, 16132 Genoa, Italy. Electronic address: [email protected].

PMID: 28958848
DOI: 10.1016/j.bmc.2017.09.023

Abstract

The NAD⁺-dependent deacetylase SIRT6 is an emerging cancer drug target, whose inhibition sensitizes cancer cells to chemo-radiotherapy and has pro-differentiating effects. Here we report on the identification of novel SIRT6 inhibitors with a salicylate-based structure. The new SIRT6 inhibitors show improved potency and specificity compared to the hit inhibitor identified in an in silico compound screen. As predicted based on SIRT6 biological roles, the new leads increase histone 3 lysine 9 acetylation and glucose uptake in cultured cells, while blocking TNF-α production and T lymphocyte proliferation. Notably, the new SIRT6 inhibitors effectively sensitize pancreatic cancer cells to gemcitabine. Finally, studies of compound fingerprinting and pharmacokinetics defined the drug-like properties of one of the new SIRT6 inhibitors, potentially allowing for subsequent in vivo proof-of-concept studies. In conclusion, new SIRT6 inhibitors with a salicylate-like structure were identified, which are active in cells and could potentially find applications in disease conditions, including cancer and immune-mediated disorders.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acetylation / drug effects
Animals
Cell Line
Cell Proliferation / drug effects
Cell Survival / drug effects
Drug Delivery Systems*
Enzyme Activation / drug effects
Enzyme Inhibitors / chemistry*
Enzyme Inhibitors / pharmacology*
Humans
Immunosuppressive Agents / chemistry
Immunosuppressive Agents / pharmacology
Inhibitory Concentration 50
Mice
Molecular Structure
Salicylates / chemistry*
Salicylates / pharmacology
Sirtuins / antagonists & inhibitors*
Sirtuins / metabolism
T-Lymphocytes / cytology
T-Lymphocytes / drug effects

Substances

Enzyme Inhibitors
Immunosuppressive Agents
Salicylates
SIRT6 protein, human
Sirtuins