4H‐CRCXL Mitigates RasV12‐Induced Phenotypes in Glioblastoma Model of Drosophila

ABSTRACT

Glioblastoma (GBM), a Grade IV malignant brain tumor, accounts for over half of all gliomas and remains resistant to current therapies, requiring the development of novel treatment strategies. Aberrant Ras signaling and PI3K/Akt hyperactivation and RAF/MEK/ERK pathways are major oncogenic drivers, implicated in approximately 30% of cancers, including GBM. Chromenes, particularly 4H‐chromenes, possess diverse anticancer activities, but their application in GBM remains limited. In this study, we evaluated the efficacy of a novel chromene derivative, ethyl 4‐(3,5‐dichloro‐2‐hydroxyphenyl)‐5,7‐dihydroxy‐2‐methyl‐4H‐chromene‐3‐carboxylate (4H‐CRCXL), using a Drosophila melanogaster model of RasV12‐driven gliomagenesis. In silico docking revealed strong interactions of 4H‐CRCXL with Ras, p‐Akt, p‐ERK, and Bcl‐2, suggesting multi‐targeted inhibition. In vivo administration of 4H‐CRCXL resulted in significant phenotypic rescue, improved CNS morphology, enhanced survival, and attenuated RAS‐driven tumor phenotypes. The compound suppressed glial hyperproliferation, reduced oxidative stress, restored metabolic homeostasis, and induced apoptosis, demonstrating a broad spectrum of anticancer effects. These findings highlight 4H‐CRCXL as a promising lead compound for targeting RAS‐driven gliomagenesis and support its further evaluation in mammalian glioma models.