JZY‑2233: A PSMA‑Targeted Degrader‑Antibody Conjugate for Advanced Prostate Cancer

Researchers have developed a new targeted therapy for advanced prostate cancer called JZY‑2233, a degrader‑antibody conjugate that homes in on prostate‑specific membrane antigen (PSMA) while delivering a highly potent CBP/p300 degrader directly to tumor cells. CBP and p300 are transcriptional coactivators that help the androgen receptor drive oncogenic gene programs in prostate cancer, and small‑molecule degraders against these proteins have shown strong antitumor activity in preclinical models. However, systemic exposure to these degraders can cause significant toxicity in normal tissues, particularly in the hematopoietic system, which has limited their clinical translation. JZY‑2233 aims to solve this problem by linking the degrader payload to an anti‑PSMA antibody, so that degradation of CBP/p300 is concentrated in PSMA‑positive prostate cancer cells rather than distributed throughout the body.

In laboratory tests, JZY‑2233 demonstrated robust antiproliferative effects in VCaP and LNCaP prostate cancer cell lines, with picomolar IC50 values that underscore the extreme potency of the payload. The conjugate maintained its ability to induce CBP/p300 degradation in these cells, leading to marked suppression of downstream oncogenic outputs such as c‑Myc and PSA. When moved into in vivo models, a single dose of JZY‑2233 at 10 mg/kg produced complete tumor suppression in LNCaP xenografts that lasted more than 90 days, an effect that significantly exceeded that seen with the unconjugated parent degrader. Pharmacodynamic analyses showed sustained loss of CBP/p300 protein and persistent downregulation of c‑Myc and PSA in tumor tissue, with measurable effects detectable up to 168 hours after dosing, indicating deep and durable target engagement within the tumor.

Importantly, this tumor‑focused delivery also translated into a more favorable safety profile. Studies in the same xenograft models reported that JZY‑2233 markedly reduced systemic toxicity compared with the unconjugated degrader, suggesting a wider therapeutic window. By restricting the degrader’s action to PSMA‑expressing cells, the conjugate appears to spare many CBP/p300‑dependent normal tissues that would otherwise be exposed with a freely circulating small‑molecule agent. This combination of prolonged tumor suppression and reduced off‑target toxicity positions JZY‑2233 as a promising candidate for evaluation in patients with advanced, PSMA‑positive prostate cancer, particularly those who have progressed on standard androgen‑receptor–targeted therapies.

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