ZM484

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.