CBPD‑409, an Oral CBP/p300 Degrader for Advanced Prostate Cancer

CBPD‑409 is an experimental, oral medicine designed to remove two helper proteins, CBP and p300, that prostate tumors use to turn cancer‑driving genes on. These proteins partner with the androgen receptor (AR), the key signal that fuels most prostate cancers, especially in the advanced, treatment‑resistant setting. By tagging CBP and p300 for destruction, a strategy known as PROTAC degradation, CBPD‑409 aims to shut down the cancer’s control centers (enhancers) rather than just partially blocking them.​

In head‑to‑head lab tests, CBPD‑409 degraded CBP/p300 quickly and potently, and it outperformed earlier drugs that only inhibit one part of these proteins (such as CCS1477 or GNE‑049). It was also effective when given by mouth in animal studies, achieving deep target knockdown in tumors and stronger tumor growth control than those older inhibitor drugs or even enzalutamide when each was used alone.​

A central reason it looks promising is its focus on “enhancers”, short DNA regions that strongly boost cancer gene programs. In AR‑positive prostate cancer, enhancer activity relies on CBP/p300, and a specific histone marker they create (called H2BNTac) is noticeably higher in tumors than in normal prostate tissue. By degrading CBP/p300, CBPD‑409 erases this enhancer signal, which more completely quiets AR‑driven genes than standard inhibitors can.​

Selectivity also stands out. In preclinical work, CBPD‑409 hit AR‑positive prostate cancer cells hard but had little to no effect on AR‑negative or neuroendocrine models, suggesting it targets the biology most relevant to hormone‑driven disease while sparing other tissues. The data also showed an expected “hook effect” at very high concentrations, a known feature of PROTACs, without changing the overall conclusion about potency.​

Perhaps most encouraging, CBPD‑409 combined very well with enzalutamide, a widely used AR‑pathway therapy. In multiple treatment‑resistant models, the combination led to deeper tumor control than either drug alone, including tumor regressions in more than half of animals in a castration‑resistant VCaP model. This synergy likely reflects a one‑two punch: enzalutamide turns off AR’s signal at the receptor, while CBPD‑409 dismantles the enhancer machinery that keeps AR‑driven genes active.​

Tolerability in preclinical studies has been favorable so far. Systemic p300/CBP degradation was reported without obvious toxicity, and importantly, this approach did not show the platelet or gut side effects that can limit some epigenetic drugs in this space, though careful human testing will be essential to confirm safety.​

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