Integrated screening for small molecules interfering with PKM2: a drug repurposing strategy against glioblastoma

Background: Glioblastoma (GBM), the most aggressive adult brain tumor, remains a significant clinical challenge. Pyruvate Kinase M2 (PKM2), by shifting between its tetrameric (metabolic) and dimeric (oncogenic) forms, drives GBM metabolism and tumorigenesis, regulating the Warburg effect. This study explores a drug repurposing strategy to identify clinically approved medications capable of stabilizing PKM2 in its tetrameric form, thus disrupting GBM metabolic adaptability and oncogenic potential.

Methods: We employed a multi-step screening strategy that integrates virtual screening, pharmacological data analysis, and in vitro cellular assays performed on anchorage-dependent and -independent GBM cell lines. This methodological process highlights the potential of repurposable drugs to target a cancer-specific metabolic vulnerability, thereby accelerating the development of novel therapeutic strategies for GBM.

Results: From thousands of clinically approved drugs, we selected, among those potentially able to cross the blood-brain barrier, three candidates that significantly inhibited GBM cell viability, reduced PKM2 nuclear localization, and impaired glycolytic activity, suggesting their potential to attenuate the Warburg effect and tumor malignancy.

Conclusions: We established a detailed screening protocol for drug repurposing to treat GBM. This approach targets a critical vulnerability of GBM cells by disrupting their bioenergetic balance. Since metabolic reprogramming and the associated Warburg effect are hallmarks of many cancers, not just GBM, we believe this approach holds significant potential for use against a wider range of tumors.

Drug repurposing; Drug screening; Glioblastoma; PKM2.