OP21IDENTIFICATION OF NOVEL SMALL MOLECULE INHIBITORS OF THE FANCONI ANAEMIA DNA REPAIR PATHWAY AS A MEANS TO SENSITISES GLIOBLASTOMAS TO CHEMOTHERAPEUTIC AGENTS

INTRODUCTION: The treatment of glioblastoma (GBM) remains a significant challenge, highlighting a critical need for the development of novel targets and agents to improve GBM treatment. We have previously shown that unlike normal brain tissue, GBMs re-express an active Fanconi Anaemia (FA) DNA repair pathway that confers resistance to Temozolomide. Additionally, we have demonstrated that drug-like small molecule disruption of the FA pathway renders GBMs more sensitive to the cytotoxic effects of Temozolomide. Our previous findings therefore highlight a potential exploitable therapeutic window to improve the clinical management of GBM and patient survival. This prompted us to develop rationally developed specific and potent small molecule inhibitors of the FA pathway for potential future clinical assessment. METHOD: In silico chemical docking, cell-based immunofluorescence and western blot analyses in various GBM cell models were used to identify novel small molecule inhibitors of the FA pathway. RESULTS: A novel chemical series of approximately 2000 compounds was interrogated both in silico and in vitro for the ability to disrupt the activity of the FA pathway. From these analyses 3 compounds were selected for further study. All 3 compounds showed a specific and potent ability inhibit the FA pathway in established and primary GBM cell models. Importantly, pre-treatment of GBM cells with these compounds conferred a potent increased sensitive to Temozolomide. CONCLUSION: We have identified novel small molecule inhibitors of the FA pathway that can be pre-clinically and clinically developed as a means to augment the anti-cancer effects of Temozolomide in GBM through an exploitable therapeutic window.