Combining repositioning and de novo synthesis of pyrazolo[3,4-d]pyrimidines to discover potent SIRT-2 inhibitors

Sirtuins (SIRTs) are a class of enzymes labelled as class III histone deacetylases. In mammals, seven isoforms (SIRT-1 to SIRT-7) are known, and they seem to act as oncopromoters or oncosuppressors, depending on the sirtuin and the cancer type. The discovery of sirtuins inhibitors (SIRTIs) has earned consideration not only for their possible application for cancer but also for diabetes, immune system clutters, and neurological illnesses. Recently, we applied a repurposing approach to our in-house library of pyrazolo[3,4-d]pyrimidines originally developed as Src and/or Abl kinase inhibitors. Two rounds of modelling studies and biological assay led us to the identification of a few SIRT-2 inhibitors. In parallel, starting from the X-ray crystal structure of some of these ligands (e.g., compound 1,) with SIRT-2, we carried out further in silico studies and individuated a family of derivatives potentially active as SIRTIs. The compounds have been synthesized and submitted to biological assays. Overall, we discovered a hit compound endowed with nanomolar activity towards SIRT-2. Biological data and structure-activity relationship evaluation will be discussed.