Two novel SIRT1 activators, SCIC2 and SCIC2.1, enhance SIRT1-mediated effects in stress response and senescence

ABSTRACT

SIRT1, a NAD⁺-dependent deacetylase, is the most well-studied member of class III histone deacetylases. Due to its wide range of activities and substrate targets, this enzyme has emerged as a major regulator of different physiological processes. However, SIRT1-mediated alterations are also implicated in the pathogenesis of several conditions, including metabolic and neurodegenerative disorders, and cancer. Current evidence highlights the potential role of SIRT1 as an attractive therapeutic target for disease prevention and treatment strategies, thus propelling the development of new pharmacological agents. By high-throughput screening of a large library of compounds, we identified SCIC2 as an effective SIRT1 activator. This small molecule showed enzymatic activity of 135.8% at 10 μM, an AC₅₀ value of 50 ± 1.8 µM, and bound SIRT1 with a K_D of 26.4 ± 0.6 μM. In order to potentiate its SIRT1-activating ability, SCIC2 was subjected to modelling studies, leading to the identification of a more potent derivative, SCIC2.1. SCIC2.1 displayed higher SIRT1 activity (175%; AC₅₀ = 36.83 ± 2.23 µM), stronger binding to SIRT1, and greater cell permeability than SCIC2. At cellular level, both molecules did not alter the cell cycle progression of cancer cells and normal cells, and were able to strengthen SIRT1-mediated effects in stress response. Finally, SCIC2 and SCIC2.1 attenuated induction of senescence by reducing senescence-associated β-galactosidase activity. Our findings warrant further investigation of these two novel SIRT1 activators in in vivo and human studies.

KEYWORDS:

• Sirtuins
• drug discovery
• epigenetic modulators
• stress response
• senescence

Availability of data and materials

All original data are available from the authors upon request.

Authors’ contributions

LA and AN: conception of the work. LS, FS, VC: experimental study, data analysis, and interpretation. SC and SDM: molecular modeling and human serum stability studies. LC and AdA: H9c2 cell studies. GS and AF: SPR and stability experiments. LA, AN and LS: writing of the manuscript. All authors read and approved the final manuscript.

Acknowledgments

The authors thank Alfonso Ciotta for help with compound screening and Catherine Fisher for language editing.

Consent for publication

No parts of this manuscript are being considered for publication elsewhere.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work was supported by the VALERE: Vanvitelli per la Ricerca Program, the Italian Flagship Project EPIGEN, PRIN-20152TE5PK, the Italian Association for Cancer Research (AIRC-17217), iCURE (CUP B21c17000030007), Campania Regional Government FASE 2: IDEAL (CUP B63D18000560007), and the Italian Ministry of Health (GR-2018-12366268).