Abstract 1693: Elraglusib (9-ING-41), a glycogen synthase kinase-3β inhibitor in combination with imipridones for treatment of solid cancer

Abstract Glycogen Synthase Kinase-3 (GSK-3) is a serine/threonine kinase with multiple biological roles, including cancer progression, therapeutic resistance and immune regulation. The GSK3β inhibitor elraglusib has shown promising preclinical and clinical activity in multiple tumor types. Previous studies demonstrated that GSK3 inhibitors can sensitize cancer cells to TRAIL-mediated apoptosis and downregulate the NF-κB pathway. Imipridones are a family of small molecule compounds that induce Death Receptor 5 and tumor necrosis factor (TNF)-related-apoptosis inducing ligand (TRAIL), causing cell death in multiple cancer models; the compounds can also inhibit the NF-κB pathway. We hypothesized that combining these two compounds would enhance anti-tumor activity. Ovarian, GBM, pancreatic, and colorectal cancer cell lines were treated with the novel drug combination of elraglusib and imipridone ONC206. CellTiter-Glo viability assays were performed after 72 hours to investigate the combinational treatment synergy. The combination treatment showed synergy in ovarian cancer (TOV21G, A2780, SKOV3), glioblastoma (SNB19, U251, LN229), pancreatic cancer (Capan-1), and colorectal cancer (HCT116) cell lines. In pancreatic and colorectal cancer cell lines, synergy was also investigated and observed between elraglusib and imipridone ONC212. Western blot analysis was performed to investigate the combinatorial effects. Single and combination treatments showed decreased expression of NF-κB p65 , anti-apoptotic proteins MCL-1 and survivin in cancer cells. Our ongoing studies are exploring other potential mechanisms of synergy and effects on immune-mediated killing of cancer cells. Our results show a potentially effective new combination of Elraglusib and Imipridones that can be further developed for cancer treatment. Citation Format: Maryam Ghandali, leiqing Zhang, Benedito A. Carneiro, Wafik S. El-Deiry. Elraglusib (9-ING-41), a glycogen synthase kinase-3β inhibitor in combination with imipridones for treatment of solid cancer [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 1693.