Forma Therapeutics, Inc, 300 N Beacon St, Watertown, MA, 02472, USA.
Arpeggio Bio, Boulder, CO, USA.
Target Oncol. 2023 Mar;18(2):269-285. doi: 10.1007/s11523-023-00949-7. Epub 2023 Feb 24.
Patients with triple-negative breast cancer (TNBC) expressing the androgen receptor (AR) respond poorly to neoadjuvant chemotherapy, although AR antagonists have shown promising clinical activity, suggesting these tumors are AR-dependent. cAMP responsive element binding protein (CREB)-binding protein (CBP) and p300 are transcriptional co-activators for the AR, a key driver of AR+ breast and prostate cancer, and may provide a novel therapeutic target in AR+ TNBC.
The aim of this study was to determine the therapeutic potential of FT-6876, a new CBP/p300 bromodomain inhibitor, in breast cancer models with a range of AR levels in vitro and in vivo.
Effects of FT-6876 on the CBP/p300 pathway were determined by combining chromatin immunoprecipitation (ChIP) with precision run-on sequencing (PRO-seq) complemented with H3K27 acetylation (Ac) and transcriptional profiling. The antiproliferative effect of FT-6876 was also measured in vitro and in vivo.
We describe the discovery of FT-6876, a potent and selective CBP/p300 bromodomain inhibitor. The combination of ChIP and PRO-seq confirmed the reduction in H3K27Ac at specific promoter sites concurrent with a decrease in CBP/p300 on the chromatin and a reduction in nascent RNA and enhancer RNA. This was associated with a time- and concentration-dependent reduction in H3K37Ac associated with a decrease in AR and estrogen receptor (ER) target gene expression. This led to a time-dependent growth inhibition in AR+ models, correlated with AR expression. Tumor growth inhibition was also observed in AR+ tumor models of TNBC and ER+ breast cancer subtypes with consistent pharmacokinetics and pharmacodynamics.
Our findings demonstrate FT-6876 as a promising new CBP/p300 bromodomain inhibitor, with efficacy in preclinical models of AR+ breast cancer.
表达雄激素受体 (AR) 的三阴性乳腺癌 (TNBC) 患者对新辅助化疗反应不佳，尽管 AR 拮抗剂显示出有前景的临床活性，这表明这些肿瘤依赖于 AR。cAMP 反应元件结合蛋白 (CREB) 结合蛋白 (CBP) 和 p300 是 AR 的转录共激活因子，是 AR+乳腺癌和前列腺癌的关键驱动因素，并且可能成为 AR+TNBC 的新治疗靶点。
本研究旨在确定新型 CBP/p300 溴结构域抑制剂 FT-6876 在体外和体内具有一系列 AR 水平的乳腺癌模型中的治疗潜力。
通过结合染色质免疫沉淀 (ChIP) 与精确运行测序 (PRO-seq)，并辅以 H3K27 乙酰化 (Ac) 和转录谱分析，确定 FT-6876 对 CBP/p300 通路的影响。还在体外和体内测量了 FT-6876 的抗增殖作用。
我们描述了 FT-6876 的发现，这是一种有效的和选择性的 CBP/p300 溴结构域抑制剂。ChIP 和 PRO-seq 的结合证实了在特定启动子位点上 H3K27Ac 的减少与染色质上 CBP/p300 的减少以及新生 RNA 和增强子 RNA 的减少同时发生。这与 AR 和雌激素受体 (ER) 靶基因表达减少相关联，并且与 H3K37Ac 的时间和浓度依赖性减少相关联。这导致了 AR+模型的时间依赖性生长抑制，与 AR 表达相关。在 AR+TNBC 和 ER+乳腺癌亚型的肿瘤模型中也观察到肿瘤生长抑制，具有一致的药代动力学和药效学。
我们的研究结果表明，FT-6876 是一种很有前途的新型 CBP/p300 溴结构域抑制剂，在 AR+乳腺癌的临床前模型中具有疗效。
