Abstract 6048: Targeting AR positive prostate cancer cells by the novel P300/CBP oral available PROTAC degrader

Abstract Background The Androgen Receptor (AR) serves as the core lineage-specific transcription factor for prostatic epithelial cells. Targeting AR is currently the most promising therapeutic strategy. However, the inevitable development of acquired resistance to anti-androgen treatments underscores the urgent need to devise new therapeutic strategies. Recent studies have revealed that in prostate cancer cells, AR is hijacked by oncogenic transcription factors, such as FOXA1 and HOXB13, which promiscuously bind to distinct enhancer sites, driving the progression of prostate cancer. This process leads to the formation of a substantially rewired AR cancer specific enhanceosome, requiring a variety of coregulators to exhibit oncogenic driver characteristics, which can be potential therapeutic targets for prostate cancer. Histone acetyltransferases (HATs) P300 and CBP are paralogs which play dominant roles in orchestrating high-order chromatin structures and transcription factor complexes by acetylating histone proteins at multiple residuals. Although accumulating evidence suggests that P300/CBP function as AR coregulator and targeting P300/CBP can markedly suppress AR-positive prostate cancer cell growth, including growth of castration-resistant prostate cancer (CRPC), most of the P300/CBP inhibitors have performed poorly in clinical trials. Methods We developed a novel P300/CBP dual oral available PROTAC degrader, namely CBPD-409. The on-target effects of CBPD-409 were assessed by quantitative proteomics (TMT-mass spectrometry) in prostate cancer cell lines. The RNA-seq analysis was conducted to investigate CBPD-409 effects on global transcriptome in prostate cancer cells. The cytotoxicity of CBPD-409 in multiple prostate cancer cell lines was examined by cell-titer-glo and incucyte assays. Conclusion In multiple cell lines, CBPD-409 exhibits remarked potency to degrade both P300 and CBP proteins in time and does dependent manner, without evident off-target effects. By employing CBPD-409, we demonstrate that degrading P300/CBP preferentially suppress AR+ prostate cancer cell growth. The global transcriptomic profiling in CBPD-409 treated prostate cancer cells revealed that loss of P300/CBP results in remarkedly downregulation of AR, Myc, FOXA1 and ERG signaling. Assessment of CBPD-409 cytotoxicity in a panel prostate cancer cell lines suggests that AR positive prostate cancer cells display highest sensitivity to CBPD-409. Citation Format: Jie luo, Abhijit Prolia, Yuanyuan Qiao, Jean Tian, Rahul Mannan, Somnath Mahapatra, Zhixiang Chen, Rithvik Seri, Shaomeng Wang, Arul Chinnaiyan. Targeting AR positive prostate cancer cells by the novel P300/CBP oral available PROTAC degrader abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 6048.