Abstract 5587: <i>In silico</i> and <i>in vitro</i> analysis of imiquimod as a potential tankyrase 2 inhibitor in wnt-active cancers

Abstract Dysregulation of the Wnt signaling pathway is a prevalent molecular pathology in cancer biology. Tankyrase (TNKS) is a positive regulator of the Wnt signaling pathway, which is overexpressed in several types of cancer: including lung, breast, colorectal, pancreatic, hepatocellular, and gastric cancers. TNKS inhibitors have shown potent activity against cancer. Using molecular docking and dynamic simulations, we identified TNKS2 as a potential binding target for imiquimod, a Toll-like receptor 7 (TLR7) agonist. Imiquimod, was predicted to bind to the PARP catalytic domain of TNKS2 using the HT Docking program. The GLIDE program on the Schrodinger software was used to dock imiquimod on the TNKS2 catalytic site. Induced-fit docking scores of imiquimod at the B site of TNKS2 was -925.73, which was slightly higher when compared to -924.68 for the co-crystallized ligand, M3F. Cavity-guided blind docking using the CB Dock 2 program showed that imiquimod shared up to 16 amino acid residues in the binding pocket of TNKS2 when compared with the binding of a commercial TNKS inhibitor, XAV939. Molecular dynamic simulations were run to assess RMSD values using the Desmond package in Schrodinger. RMSD values over 100 ns showed a relatively stable interaction of imiquimod in the catalytic site of TNKS2 which was comparable to that of the co-crystallized ligand, M3F. These data suggest that imiquimod might mediate its anticancer therapeutic activities through TNKS2 inhibition as a novel molecular mechanism. In vitro studies using Wnt-active cancer cell lines are currently underway to probe the predicted in silico results. This is the first study that proposes a novel potential anticancer mechanism of Imiquimod through Wnt pathway inhibition. Citation Format: Philemon N. Ubanako, Ramesh Pandian, Adedapo Adeyinka, Clement Penny. In silico and in vitro analysis of imiquimod as a potential tankyrase 2 inhibitor in wnt-active cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5587.