Abstract 1523: Discovery and Validation of a novel small molecule metabolic inhibitor targeting glioblastoma growth

Abstract Glioblastoma (GBM) is an aggressive brain tumor with poor prognosis and limited treatment options. Pyruvate dehydrogenase kinase 1 (PDK1) plays a critical role in the metabolic reprogramming of GBM cells, making it an attractive therapeutic target. In this study, we investigated the efficacy of a novel PDK1 inhibitor, in inhibiting GBM progression. Using U87 glioblastoma cells, we demonstrated that the UIC novel inhibitor significantly reduced cell viability, induced G2/M cell cycle arrest, inhibited glycolysis, and promoted oxidative phosphorylation. In vitro assays revealed that the UIC novel inhibitor effectively suppressed U87 cell migration and invasion compared to dichloroacetate (DCA), another PDK1 inhibitor. Wound healing and transwell invasion assays showed that the UIC novel inhibitor reduced wound closure and cell invasion by 83%, outperforming DCA. Furthermore, the UIC novel inhibitor treatment increased reactive oxygen species (ROS) production and decreased lactate release, indicating a shift from glycolysis to oxidative metabolism. In vivo, intracranial implantation of U87 cells into mice followed by the UIC novel inhibitor treatment resulted in prolonged survival, delayed tumor-associated weight loss, and reduced tumor burden compared to vehicle controls. Hematoxylin and eosin (H&E) staining confirmed smaller tumor sizes in treated mice, while immunohistochemistry (IHC) revealed decreased expression of PDK1 and phosphorylated EGFR (pEGFR), key oncogenic markers in GBM. These findings suggest that the UIC novel inhibitor is a potent inhibitor of PDK1 with significant anti-tumor activity in GBM models, offering a promising therapeutic strategy for targeting metabolic vulnerabilities in GBM. Further clinical evaluation of the UIC novel inhibitor is warranted to explore its potential as a novel treatment option for glioblastoma patients. Citation Format: Maheedhara R. Guda, Andrew J. Tsung, Swapna Asuthkar, Kiran Velpula. Discovery and Validation of a novel small molecule metabolic inhibitor targeting glioblastoma growth [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 1523.