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

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.