Discovery of Novel Drug-Conjugate Molecule <b>ZM484</b> with Dual p53-MDM2 and TOP1 Inhibition for the Treatment of Colorectal Cancer

The blocking interaction between p53 and its negative regulator MDM2 is an engaging therapeutic strategy for antitumor drug development, and there are several drug candidates of p53-MDM2 inhibitors in clinical trials. In the present study, novel drug conjugates of p53-MDM2 inhibitors and topoisomerase I (TOP1) inhibitors have been designed based on bioinformatics analysis results of ten tumor tissues. Among them, ZM484 showed potent antiproliferative activity against three cell lines HCT116, SJSA-1, and A549, with the strongest p53-MDM2 and TOP1 inhibitory activity. Additionally, the treatment of compound ZM484 significantly reduced the tumor growth of HCT116 in BALB/c nude mice mode. Furthermore, our data highlighted the superior stability and good pharmacokinetic properties of compound ZM484. Using LC-MS analysis, we identified that compound ZM484 is capable of effectively releasing camptothecin (CPT) and the potent p53-MDM2 inhibitor 8a upon coincubation with DTT. Therefore, compound ZM484 could be a potential drug-conjugate candidate for the treatment of colorectal cancer.