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 alpha 5 beta 1 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) (1) was designed by coupling the MDM2 inhibitor SAR405838 to a selective alpha 5 beta 1 integrin ligand cyclo(phg-isoDGR-k) (7) 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 1, 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 alpha 5 beta 1 integrin receptor.