Prostate cancer depends on genetic "switches," called enhancers, that activate tumor‑promoting genes. Researchers at the University of Michigan Health Rogel Cancer Center discovered a key enhancer mark: histone H2B N‑terminal acetylation (H2BNTac).
They identified the proteins p300 and CBP as the enzymes that add H2BNTac, working with the androgen receptor (AR) to drive enhancer activity and cancer growth.
The study, published in Nature Genetics, shows that H2BNTac, p300, and CBP levels are higher in prostate tumors compared to normal tissue.
Functional experiments in prostate cancer cells revealed that p300 and CBP are essential for AR‑regulated active enhancers.
Building on these findings, Dr. Arul Chinnaiyan collaborated with Dr. Shaomeng Wang to develop CBPD‑409, a small molecule that selectively degrades p300 and CBP, removes H2BNTac marks, and shuts down oncogenic AR signaling. CBPD‑409 is orally active and highly potent.
"Degrading p300 and CBP removes H2BNTac at AR enhancer sites," Dr. Chinnaiyan explains. "CBPD‑409 rapidly and selectively erases this mark, unlike bromodomain inhibitors, which only partially inhibit p300/CBP."
Cells with higher H2BNTac were more sensitive to CBPD‑409, suggesting that the drug may work best in certain patient subgroups. In preclinical models of castration‑resistant prostate cancer, CBPD‑409 induced tumor regression and was well tolerated in mice.
Previous small‑molecule inhibitors of p300/CBP showed limited clinical success because they did not fully disrupt protein function.
"This highlights the need for a deeper mechanistic understanding of how p300 and CBP drive AR‑dependent growth," says Dr. Chinnaiyan. "Our study demonstrates the potential of targeted protein degradation."
Prostate cancer remains the most common cancer among U.S. men and a major cause of cancer death.
"These encouraging preclinical results support advancing a selective p300/CBP degrader into clinical trials for castration‑resistant prostate cancer," comments Dr. Wang.