Objective

Sirtuin 1 (SIRT1) is a member of the NAD+-dependent histone deacetylase (HDAc) family that plays a pivotal role in regulation of numerous cellular events, including various metabolic diseases, inflammation, neurodegeneration, the progression of cancer and metastasis, ageing and lifespan. In this work, we address the increased demand in finding small-molecule inhibitors of SIRT1 by applying Differential Scanning Fluorimetry adapted to the HTS platform. In addition, we report a creation of the focused library of SIRT1 activation loop binders (583 compounds) originated from Enamine’s 2.3 M+ small molecules collection, using computer simulation and molecular docking approach. Targeted library screening against recombinant SIRT1 resulted in generation of 15 hits, that were further investigated on their biochemical function (SIRT-Glo™ Аssay, Promega) and differential cytotoxicity against a panel of cancer cell lines.

This work resulted in identification of novel small-molecule inhibitors of SIRT1, and further reaseach is warranted to elucidate the mechanisms of their action and improvement of their pharmacological properties.