JZY-2233: An antigen-targeted CBP/p300 degrader-antibody conjugate for advanced prostate cancer therapy

Background: CBP/p300 are essential transcriptional coactivators of the androgen receptor and play a critical role in prostate cancer pathogenesis. Small-molecule CBP/p300 degraders have demonstrated potent efficacy against prostate cancer but are limited by toxicity, impeding clinical translation. Methods:To enhance tumor specificity and minimize systemic toxicity, we developed a Degrader-Antibody Conjugate (DAC) by linking a highly potent CBP/p300 degrader to a prostate-specific membrane antigen (PSMA) antibody, generating JZY-2233. In vitro antiproliferative activities were assessed using VCaP and LNCaP prostate cancer cell lines. In vivo efficacy, pharmacodynamics, and toxicity were evaluated in a LNCaP xenograft mouse model. Results: JZY-2233 induced robust growth inhibition in VCaP and LNCaP cells, with picomolar IC50 values. In vivo, treatment with JZY-2233 led to sustained CBP/p300 degradation and suppression of c-Myc and PSA in tumor tissues, with effects persisting up to 168 hours post-dose. A single administration at 10 mg/kg resulted in complete tumor suppression for over 90 days in the LNCaP model, significantly exceeding the effect of the unconjugated parent degrader. Importantly, JZY-2233 markedly reduced systemic toxicity. Conclusions: JZY-2233 is a highly potent, antigen-targeted CBP/p300-PSMA DAC, offering prolonged tumor suppression and reduced toxicity in models of advanced prostate cancer. This approach provides a strong rationale for further evaluation in clinical studies and may be adapted for targeting additional tumor antigens across diverse cancers.