Abstract 2347: Zuclopenthixol as an inhibitor of glioblastoma-induced neuronal hyperexcitability

Abstract

Abstract Introduction Drug repurposing serves as a promising avenue for glioblastoma treatment, especially as new evidence emerges about the role of neuronal activity dependent tumor proliferation. Structure based drug discovery with virtual screening requires highly accurate 3D information about the target of choice. Recent developments in machine learning based protein structure prediction have allowed for the exploration of chemical space with virtual screening tools not previously accessible via traditional methods. Netrin-G1 (NTNG1) is an axonal guidance molecule implicated in glioblastoma with high functional connectivity to the cortex. In this study, we explore pharmacologic inhibition of NTNG1 with a clinically approved compound. Methods We perform protein structure predictions with AlphaFold2, followed by structure relaxation in an explicit solvent environment with NAMD 2.14. A final confirmation of NTNG1 was used as input to an AutoDock Vina based virtual screening platform. Zuclopenthixol (ZP) was chosen from a list of hits for microelectrode array (MEA) experiments in a mouse neuron/patient-derived tumor cell co-culture environment. Results A list of clinically approved compounds were returned from our virtual screen. ZP was chosen for validation studies, as it readily crosses the blood-brain barrier and occupies the entire TSP1 binding site in NTNG1. Preliminary results from MEA studies suggest ZP reduces tumor-mediated hyperexcitability and adequately modulates a protein-protein interaction between NTNG1 and TSP1. Conclusion By demonstrating that ZP decreases tumor-mediated hyperexcitability, this study offers evidence for the novel application of ZP to reduce glioblastoma proliferation. Further work will focus on survival analyses in mice treated with ZP and validation of experimental compounds that are structurally similar to ZP. Citation Format: Mikias B. Negussie, Saritha Krishna, Ying Wei, Cesar Nava Gonzales, Mulki Mehari, Shawn L. Hervey-Jumper. Zuclopenthixol as an inhibitor of glioblastoma-induced neuronal hyperexcitability [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2347.