Discovery of Novel CBP/p300 and BRD4 Dual-Target PROTACs with Potent Antitumor Activity in Prostate Cancer

CBP/p300 and BRD4 synergistically drive prostate cancer
progression.
Here, we report the rational design, synthesis, and biological evaluation
of novel PROTACs capable of simultaneously degrading CBP/p300 and
BRD4. The representative compounds 10h and 29c induced robust degradation of both targets with DC50 values
ranging from 8.8 pM to 10.5 nM in PC-3 prostate cancer cells, accompanied
by marked downregulation of c-Myc and acetylated H3K27. Both compounds
displayed potent antiproliferative activity across multiple cancer
cell lines, with higher potency than NEO2734, paclitaxel (PTX), and
ARV-771. In a PC-3 xenograft mouse model, compound 29c achieved dose-dependent tumor growth inhibition (TGI) of up to 81.5%
at a low dose of 0.2 mg/kg, administered every other day, significantly
surpassing the efficacy of NEO2734 and PTX at higher doses. Together, 29c, a highly efficient CBP/p300 and BRD4 dual-target degrader,
demonstrates significant therapeutic potential in prostate cancer
and warrants further development.

CBP/p300与BRD4协同驱动前列腺癌进展。本研究报道了可同时降解CBP/p300与BRD4的新型蛋白降解靶向嵌合体（PROTACs）的合理设计、合成及生物学评价。代表性化合物10h与29c可在PC-3前列腺癌细胞中强效降解上述两个靶标，其DC50值范围为8.8 pM至10.5 nM，同时可显著下调c-Myc与乙酰化H3K27的表达水平。两款化合物在多种癌细胞系中均展现出强效抗增殖活性，其活性优于NEO2734、紫杉醇（PTX）及ARV-771。在PC-3细胞异种移植小鼠模型中，化合物29c以隔日给药的低剂量0.2 mg/kg即可实现最高达81.5%的剂量依赖性肿瘤生长抑制（TGI），其疗效显著优于更高剂量下的NEO2734与紫杉醇。综上，作为一款高效的CBP/p300与BRD4双靶点降解剂，29c在前列腺癌治疗中展现出可观的应用潜力，值得开展进一步开发研究。