Chemical Biology of IRP1-HIF2a Signaling

摘要 HIF 2a是由缺氧和肿瘤相关突变诱导的转录因子。HIF 2a是一种 癌症血管生成和癌症代谢的节点调节因子，干细胞发育和 它被证实是von Hippel-Lindau（VHL）缺陷性炎症的治疗靶点。 透明细胞肾细胞癌（ccRCC）。HIF 2a也与其他疾病有关， 除了ccRCC，如胶质母细胞瘤和前列腺癌。 我们鉴定了特定的HIF 2a抑制剂，并将其作为化学生物学工具， 发现这些小分子激活铁调节蛋白1（IRP 1），以抑制 HIF 2a翻译。 在本申请中，我们提出验证IRP 1作为异种移植物中HIF 2a抑制的靶标， ccRCC和VHL疾病的转基因动物模型。此外，我们建议进一步提高 通过鉴定HIF 2a的直接蛋白靶点，深入了解IRP 1-HIF信号传导的复杂性 抑制剂的最后，我们提出合成一系列HIF 2a抑制剂的衍生物，以进一步 以产生合适的化合物 用于体内临床前研究和/或用于进一步体内解剖HIF 2a生物学的工具。

ABSTRACT HIF2a is a transcription factor induced by hypoxia and tumor associated mutations. HIF2a is a nodal regulator of cancer angiogenesis and cancer metabolism, stem cell development and inflammation and it is validated as a therapeutic target in von Hippel-Lindau (VHL)-deficient clear cell renal cell carcinoma (ccRCC). HIF2a had also been implicated in other diseases, beyond ccRCC, such as glioblastoma and prostate cancer. We identified specific HIF2a inhibitors and, by using them as chemical biology tools, we discovered that these small molecules activate Iron Regulatory Protein 1 (IRP1) to suppress HIF2a translation. In this application we propose to validate IRP1 as a target for HIF2a inhibition in xenograft and transgenic animal models of ccRCC and VHL disease. In addition, we propose to gain further insights into the complexity of IRP1-HIF signaling by identifying the direct protein target of HIF2a inhibitors. Finally, we propose to synthesize a series of derivatives of HIF2a inhibitors to further improve their potency and physicochemical properties in order to generate compounds suitable for in vivo preclinical studies and/or tools for further in vivo dissection of HIF2a biology.