Background: In advanced prostate cancer, the paralog transcription co-activators p300/CBP are often highly expressed and have been associated with disease progression and poor prognosis. While several inhibitors of the bromo- and histone acetyltransferase domains of p300/CBP have been described, past efforts to develop drug-like ligands of other regions of this attractive target have been unsuccessful. Methods: A rationally designed small molecule modulator of the CH1-domain of p300/CBP was tested in a panel of prostate cancer cell lines, followed by cell cycle analysis and beta-galactosidase staining. Inhibition of the p300-dependent androgen receptor (AR) related transcriptional response was determined in a luciferase reporter assay and by qPCR analysis of expression of downstream genes like prostate-specific antigen (PSA), transmembrane protease-serine 2 (TMPRSS2) and prostein (SLC45A3). In vivo effects were evaluated in cell line- and patient-derived xenograft models of CRPC. Results: Selective blockage of the CH1 domain of p300/CBP results in sustainable anti-proliferative effects in AR-positive and AR-negative prostate cancer cells inducing apoptosis and/or senescence. Transcriptome and gene expression analyses revealed the downregulation of various drivers of cell cycle progression as well as decreased expression of hormone-induced, AR-regulated genes. In enzalutamide-resistant xenograft models of CRPC, oral administration of the compound triggered tumor regression/eradication at well tolerated doses. Serum PSA levels were strongly decreased in treated animals. Conclusions: Simultaneous inhibition of both, AR-signaling and downregulation of p300/CBP activity, may cause profound and long lasting antitumoral effects in patients with advanced prostate cancer. Future clinical investigation of this novel oral small molecule agent is warranted.