Human murine double minute 2 (Mdm2) protein is a primary, endogenous cellular inhibitor of the tumor suppressor p53 through their direct protein-protein interaction, which makes it and an attractive cancer therapeutic target. Although highly potent and specific small-molecule inhibitors of Mdm2-p53 protein-protein interaction were discovered in the past decades with several of them in clinical development for cancer treatment, activation of p53 by Mdm2 inhibitors leads to dramatically upregulation of Mdm2 mRNA and accumulation of Mdm2 protein since Mdm2 is a direct transcriptional target of p53. Dramatic upregulation of Mdm2 protein by Mdm2 inhibitors not only limit their potential clinical efficacy but also may have unwanted deleterious effects due to the oncogenic activity of Mdm2 protein. In present study, we have designed and synthesized several proteolysis-targeting chimera (PROTAC) small-molecule molecules to induce the degradation of Mdm2 protein and investigated their therapeutic potential and mechanism of action in vitro and in vivo. Our best Mdm2 degrader (LE-004) could effectively induce Mdm2 degradation in leukemia cells at as low as 1 nM within 1 hour. Degradation of Mdm2 induced by LE-004 could effectively induce accumulation of wild-type p53 protein and activate of p53 transcriptional activity in leukemia cells without accumulation of Mdm2 protein. LE-004 could potently inhibit cell growth and induce apoptosis in leukemia cells in low nano-molar concentrations, which is 10-100 times more effective than the Mdm2 inhibitors. The PD and efficacy studies have shown that LE-004 could strongly activate wild-type p53 in xenograft AML tumor tissues in mice and achieve complete tumor regression in mice at well-tolerated dose-schedules in mice. In conclusion, PROTAC designed Mdm2 degraders could successfully induce Mdm2 degradation and corresponding cancer cell growth inhibition, which might be developed as a novel efficient strategy for cancer therapy.

PROTAC design of Mdm2 degraders: A novel efficient approach for cancer therapy

254th National Meeting (2017)

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