Tenovin-1

Tenovin-1 is a small-molecule inhibitor of the sirtuin family of NAD(+)-dependent class III histone deacetylases (HDACs), specifically targeting SIRT1 and SIRT2. It was originally identified through a chemical genetic screen for compounds capable of activating the tumor suppressor p53 without inducing DNA damage. Tenovin-1 acts by inhibiting the deacetylase activity of sirtuins, which leads to increased acetylation and transcriptional activity of p53. In preclinical research, particularly in melanoma models, Tenovin-1 has demonstrated significant anti-proliferative and pro-apoptotic effects by reducing SIRT1 protein levels and enhancing p53-mediated cell death. While it is a potent research tool for studying epigenetic regulation and sirtuin biology, its clinical development has been limited by low aqueous solubility, which led to the synthesis of more soluble analogs such as Tenovin-6.