A novel quinazolinone insulin receptor inhibitor and its synergy with an EGFR inhibitor in glucose-driven glioblastoma.

Aberrant signaling through insulin-like growth factor 1 receptor (IGF1R) and epidermal growth factor receptor (EGFR) drives glioblastoma (GBM) progression and therapy resistance. Herein, we describe the synthesis and biological evaluation of W1B, a novel styrylquinazolinone-based small-molecule inhibitor. In antiproliferative assays, W1B exhibited potent submicromolar activity against a panel of GBM cell lines. Kinase assays and binding studies confirmed strong inhibition and high binding affinity toward IGF1R. Molecular docking suggested possible interactions with both IGF1R and EGFR, with W1B adopting distinct binding poses in each kinase domain. In cellular studies, W1B reduced IGF1R and EGFR protein levels in LN229 cells and suppressed Akt phosphorylation. Under high-glucose conditions, however, W1B only retained inhibitory activity toward IGF1R, resulting in attenuated effects on the Akt/mTOR axis and underscoring the influence of glucose-dependent signaling rewiring on drug efficacy. Combination studies revealed that W1B acts synergistically with the EGFR inhibitor dacomitinib, effectively overcoming compensatory activation of parallel pathways. Biomimetic lipophilicity and in silico pharmacokinetic analyses indicated that styrylquinazolinone has the potential to cross the blood-brain barrier (BBB). The in vivo studies on Danio rerio have shown a good safety profile, as well as strong antitumor potential of the tested compound. Therefore, these findings establish W1B as a promising derivative for the development of next-generation dual IGF1R/EGFR inhibitors in GBM.