Design, synthesis and biological activity evaluation of novel inhibitors targeting TNKS2, based on docking, virtual screening and molecular dynamics simulation studies

In recent years, tankyrases (TNKS) have garnered substantial interest as a promising new drug target. An escalating amount of research has been dedicated to the development of TNKS-targeting drugs, highlighting the substantial potential in anti-cancer therapeutics. In this study, a potential TNKS2 lead compound, ZINC11726230, was identified through docking-based virtual screening, molecular dynamics simulation and bioassay. Structural modification of the lead compound, ZINC11726230, yielded two new TNKS2 inhibitors (compound 1-2), which exhibited remarkable inhibitory activity, with an IC50 value of 0.013 μM, outperforming the positive control compound G007-LK (IC50 = 0.035 μM). This study offers unique insights into the discovery of effective TNKS2 inhibitors.