PO.ET09.02 · 实验与分子治疗
FHT-171的临床前特征鉴定：一种针对CBP依赖性实体瘤中CREB结合蛋白（CBP）的首创降解剂
Preclinical characterization of FHT-171, a first-in-class degrader targeting CREB-binding protein (CBP) in CBP-dependent solid tumors
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
同源赖氨酸乙酰转移酶CREB结合蛋白（CBP）和E1A结合蛋白P300（EP300）作为转录共激活因子发挥作用，调控多种细胞程序。功能性筛选揭示了这两个同源物在肿瘤细胞生物学中存在双向合成关系。这种合成致死关系为在EP300突变型以及其他CBP依赖性癌症中选择性靶向CBP提供了治疗机会。在此，我们提出对一种首创的选择性CBP降解剂FHT-171的全面临床前评估，该降解剂旨在靶向实体瘤中的转录共激活因子依赖性。通过一系列体外和体内研究，我们表征了该化合物的生化选择性、细胞降解动力学、转录影响、抗肿瘤疗效以及在多种实体瘤模型中的耐受性。这些发现为CBP降解的治疗潜力提供了机制学和非临床转化的洞见，并支持进一步开发这一新型作用模式用于治疗CBP依赖性恶性肿瘤。
查看英文原文 English abstract
The paralog lysine acetyltransferases CREB-binding protein (CBP) and E1A-binding protein P300 (EP300) function as transcriptional coactivators that regulate diverse cellular programs. Functional screens have revealed a bidirectional synthetic relationship between these two paralogs in tumor cell biology. This synthetic lethal relationship offers a therapeutic opportunity in selectively targeting CBP in EP300 -mutant as well as other CBP-dependent cancers. Herein, we present a comprehensive preclinical evaluation for a first-in-class, selective CBP degrader, FHT-171, designed to target transcriptional co-activator dependencies in solid tumors. Through a series of in vitro and in vivo studies, we characterize the compound's biochemical selectivity, cellular degradation kinetics, transcriptional impacts, antitumor efficacy and tolerability across multiple solid tumor models. These findings provide mechanistic and non-clinical translational insight into the therapeutic potential of CBP degradation and support further development of this novel modality for the treatment of CBP-dependent malignancies.
利益披露 Disclosure
D. Sappal, None..
M. M. Wilson, None..
L. La Bonte, None..
M. Lin, None..
B. Bullock, None.