2. Academic Validation
  3. Discovery of Novel Drug-Conjugate Molecule ZM484 with Dual p53-MDM2 and TOP1 Inhibition for the Treatment of Colorectal Cancer

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

  • J Med Chem. 2025 Sep 25;68(18):18988-19001. doi: 10.1021/acs.jmedchem.5c01003.
Chuanhao Wang 1 2 3,  Baobao Chen 3,  Hang Yang 1 2,  Chengyi Huang 4,  Yanming Zhang 1,  Jianyu Yan 1,  Daozuan Zhang 3,  Anhua Huang 3,  Yuelin Wu 3,  Junwu Zhu 2,  Chunlin Zhuang 1 5,  Zhenyuan Miao 1
Affiliations

Affiliations

  • 1 School of Pharmacy, Second Military Medical University, Shanghai 200433, P. R. China.
  • 2 School of Chemistry and Chemical Engineering, Nanjing University of Science and Technology, Nanjing 210094, P. R. China.
  • 3 School of Chemical and Environmental Engineering, Shanghai Institute of Technology, Shanghai 201418, P. R. China.
  • 4 Department of Radiation Oncology, Changhai Hospital Affiliated to Naval Medical University, Shanghai 200433, P. R. China.
  • 5 School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang 453007, P. R. China.
PMID: 40906370 DOI: 10.1021/acs.jmedchem.5c01003
Abstract

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.

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