Synthesis and Biological Evaluation of a Novel Dual-Targeting Small Molecule Drug Conjugate Modulating the Crosstalk between α5β1 Integrin and MDM2 in Glioblastoma

Negative crosstalk between α5β1 integrin and the p53-MDM2 regulatory axis contributes to glioblastoma progression and therapeutic resistance. To explore the potential of dual inhibition of these two biological targets, the dual targeting small molecule drug conjugate (SMDC) (<b>1</b>) was designed by coupling the MDM2 inhibitor SAR405838 to a selective α5β1 integrin ligand <i>cyclo</i>(phg-<i>iso</i>DGR-<i>k</i>) (<b>7</b>) through a stable chemical linker. The resulting conjugate retained antiproliferative activity in U87-MG glioblastoma cells and induced p53 reactivation with minimal MDM2 induction. Cell cycle distribution analysis revealed a redistribution of cells from the G0/G1 phase to the G2/M phase exclusively upon treatment with conjugate <b>1</b>, suggesting that a different mechanism of action is engaged. These findings support the potential of this dual-targeting approach through a dual-targeting SMDC as a promising therapeutic strategy against high-grade glioma overexpressing the α5β1 integrin receptor.