通过抗体药物偶联物在前列腺癌细胞中靶向降解p300和CBP

p300 and CBP contribute to Androgen Receptor (AR) driven transcriptional programs that support castration-resistant prostate cancer, and their elevated expression has been associated with aggressive disease. p300 and CBP, paralog histone acetyltransferases (HATs), function as co-activators to transcription factors including AR and c-Myc. These enzymes play an essential role in regulating cell growth by acetylating substrates such as AR and histone residues including Histone-3-Lysine 27 (H3K27). Targeting p300 and CBP is an emerging therapeutic strategy in prostate cancer, particularly in disease settings where AR transcriptional activity mediates resistance to current standard of care. Preclinical studies have shown p300 and CBP inhibitor efficacy in metastatic castration-resistant prostate cancer (mCRPC) models. Unfortunately, clinical evaluation of p300 and CBP inhibitors has identified hematologic toxicities including neutropenia, thrombocytopenia, and anemia. These effects are thought to result from disruption of chromatin remodeling and transcriptional programs that are essential for platelet production, red blood cell (RBC) formation and immune cell development. Intermittent dosing schedules, designed to circumvent thrombocytopenia, demonstrate sub-optimal anti-tumor activity due to reduced drug exposure in plasma. In our studies, we demonstrate the use of ADCs to target antigens expressed on prostate cancer cell lines, facilitating the delivery of payloads that degrade p300/CBP via cereblon-mediated ternary complex formation. We have identified a potent p300 and CBP degrader (BRSD056) with a DC 50 of 1 nM in a 22Rv1-p300-HiBiT expression system. Treatment of VCaP and LnCaP with BRSD056 led to cell growth inhibition with a GI 50 of 0.48 and 17 nM, respectively. Furthermore, BRSD056 modulated H3K27ac, AR, c-Myc, and FOXA1 protein levels, and increased apoptosis markers. An analog of BRSD056 was conjugated to antibodies targeting prostate cancer antigens B7H3 and PSMA through a cleavable linker. The anti-B7H3-BRSD056 ADC exhibited a GI 50 of 19 nM and an Amax of -29% in VCaP cells when tested in vitro . Dosing of anti-B7H3-BRSD056 resulted in tumor stasis of VCaP tumors. A second conjugate, anti-PSMA-BRSD056, led to 77% tumor growth inhibition of LnCaP tumors. Our work shows the potential of developing highly potent p300/CBP degraders that can be specifically vectorized to prostate cancer tumors, which may improve efficacy and tolerability in challenging disease settings.