Qiao Zeyu, Nguyen Long C, Yang Dongbo, Dann Christopher, Thomas Deborah M, Henn Madeline, Valdespino Andrea, Swenson Colin S, Oakes Scott A, Rosner Marsha Rich, Moellering Raymond E
Department of Chemistry, The University of Chicago, Chicago, IL, USA.
Institute for Genomics and Systems Biology, The University of Chicago, Chicago, IL, USA.
Nat Chem Biol. 2025 Feb;21(2):247-255. doi: 10.1038/s41589-024-01716-z. Epub 2024 Aug 30.
Many oncogenic transcription factors (TFs) are considered to be undruggable because of their reliance on large protein-protein and protein-DNA interfaces. TFs such as hypoxia-inducible factors (HIFs) and X-box-binding protein 1 (XBP1) are induced by hypoxia and other stressors in solid tumors and bind to unfolded protein response element (UPRE) and hypoxia-induced response element (HRE) motifs to control oncogenic gene programs. Here, we report a strategy to create synthetic transcriptional repressors (STRs) that mimic the basic leucine zipper domain of XBP1 and recognize UPRE and HRE motifs. A lead molecule, STR22, binds UPRE and HRE DNA sequences with high fidelity and competes with both TFs in cells. Under hypoxia, STR22 globally suppresses HIF1α binding to HRE-containing promoters and enhancers, inhibits hypoxia-induced gene expression and blocks protumorigenic phenotypes in triple-negative breast cancer (TNBC) cells. In vivo, intratumoral and systemic STR22 treatment inhibited hypoxia-dependent gene expression, primary tumor growth and metastasis of TNBC tumors. These data validate a novel strategy to target the tumor hypoxia response through coordinated inhibition of TF-DNA binding.
许多致癌转录因子（TFs）因其依赖于大的蛋白质-蛋白质和蛋白质-DNA界面而被认为是不可成药的。诸如缺氧诱导因子（HIFs）和X盒结合蛋白1（XBP1）等转录因子在实体瘤中由缺氧和其他应激源诱导，并与未折叠蛋白反应元件（UPRE）和缺氧诱导反应元件（HRE）基序结合，以控制致癌基因程序。在此，我们报告了一种创建合成转录抑制因子（STRs）的策略，该抑制因子模仿XBP1的碱性亮氨酸拉链结构域并识别UPRE和HRE基序。一个先导分子STR22以高保真度结合UPRE和HRE DNA序列，并在细胞中与这两种转录因子竞争。在缺氧条件下，STR22全面抑制HIF1α与含HRE的启动子和增强子的结合，抑制缺氧诱导的基因表达，并阻断三阴性乳腺癌（TNBC）细胞中的促肿瘤表型。在体内，瘤内和全身给予STR22治疗可抑制TNBC肿瘤的缺氧依赖性基因表达、原发性肿瘤生长和转移。这些数据验证了一种通过协同抑制转录因子- DNA结合来靶向肿瘤缺氧反应的新策略。
