SIRT6 Inhibitors

SIRT6 inhibitors constitute a diverse array of chemical compounds designed to precisely regulate the activity of SIRT6, a crucial protein involved in various cellular processes, particularly those related to DNA repair and genomic stability. This chemical class can be broadly classified into two categories based on their distinct mechanisms of action: direct and indirect inhibitors. Direct inhibitors, exemplified by compounds like Ex-527, NCO-90, and OSS_128167, operate by targeting the catalytic domain of SIRT6. These inhibitors disrupt the deacetylase activity of SIRT6 by binding to the NAD+ binding site, leading to the accumulation of acetylated proteins. Notably, this includes proteins pivotal to DNA repair processes, thereby influencing genomic stability and cellular responses to DNA damage. The precise interference with the catalytic domain of SIRT6 provides researchers with a focused toolset for dissecting the intricacies of SIRT6 function.

Conversely, indirect inhibitors such as Quercetin, Tenovin-6, and DMA employ a different strategy by modulating specific cellular pathways. For instance, Quercetin indirectly influences SIRT6 by impacting the AMP-activated protein kinase (AMPK) pathway. It enhances the phosphorylation of AMPK, subsequently leading to the phosphorylation of SIRT6. Indirect inhibitors present a unique approach, intervening in upstream signaling pathways or protein-protein interactions critical for SIRT6 function. This broader spectrum of mechanisms not only expands the toolbox available for researchers but also facilitates a more comprehensive understanding of SIRT6's multifaceted roles in cellular processes associated with DNA repair and genomic stability. In conclusion, the diverse landscape of SIRT6 inhibitors, encompassing both direct and indirect categories, empowers researchers with a nuanced toolkit to explore the intricate functions of SIRT6 and its implications for cellular homeostasis and response to DNA damage.