Department of Pharmacology and Pharmaceutical Sciences, University of Southern California, 1985 Zonal Ave., Los Angeles, CA 90033, USA.
Biopolymers. 2011 Jan;95(1):8-16. doi: 10.1002/bip.21550.
Designed small molecule inhibitors of hypoxia-inducible gene expression have potential to become new research tools for molecular biology, genetics and serve as leads to new therapeutics. We report design, synthesis evaluation of biological activity, and a preliminary mechanistic study of epipolythiodiketopiperazine (ETP) transcriptional antagonist that targets the interaction between the C-terminal transactivation domain (C-TAD) of hypoxia-inducible factor 1α (HIF-1α) and cysteine-histidine rich region (CH1) of transcriptional coactivator p300/CBP. Our results indicate that in cultured cells synthetic ETP 3 disrupts the structure and function of this complex in a dose-dependent manner, resulting in rapid downregulation of hypoxia-inducible gene expression.
缺氧诱导基因表达的小分子抑制剂的设计有可能成为分子生物学、遗传学的新研究工具，并为新的治疗方法提供线索。我们报告了针对缺氧诱导因子 1α（HIF-1α）的 C 端反式激活结构域（C-TAD）和转录共激活因子 p300/CBP 的半胱氨酸-组氨酸丰富区（CH1）之间相互作用的新型硫代二酮哌嗪（ETP）转录拮抗剂的设计、合成、活性评估和初步机制研究。我们的结果表明，在培养细胞中，合成的 ETP3 以剂量依赖的方式破坏该复合物的结构和功能，导致缺氧诱导基因表达的快速下调。
