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 (TF) 被认为是不可成药的，因为它们依赖于大的蛋白质-蛋白质和蛋白质-DNA 界面。缺氧诱导因子 (HIF) 和 X-box 结合蛋白 1 (XBP1) 等转录因子由实体瘤中的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) 结合控制致癌基因程序的基序。在这里，我们报告了一种创建合成转录抑制子（STR）的策略，该抑制子模拟 XBP1 的基本亮氨酸拉链结构域并识别 UPRE 和 HRE 基序。先导分子 STR22 以高保真度结合 UPRE 和 HRE DNA 序列，并与细胞中的两种 TF 竞争。在缺氧条件下，STR22 全面抑制 HIF1α 与含有 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) 细胞的促肿瘤表型。在体内，肿瘤内和全身 STR22 治疗抑制缺氧依赖性基因表达、原发性肿瘤生长和 TNBC 肿瘤的转移。这些数据验证了一种通过协调抑制 TF-DNA 结合来靶向肿瘤缺氧反应的新策略。