Chemical Biology of IRP1-HIF2a Signaling

摘要 HIF2A是一种受低氧和肿瘤相关突变诱导的转录因子。HIF2A是一种 肿瘤血管生成和肿瘤代谢、干细胞发育和肿瘤代谢的结节调节因子 炎症，并被证实为von Hippel-Lindau(VHL)缺陷的治疗靶点 肾透明细胞癌(CCRCC)。HIF2A还与其他疾病有牵连， 除慢性肾细胞癌外，如胶质母细胞瘤和前列腺癌。 我们确定了特定的HIF2A抑制剂，并将它们用作化学生物学工具，我们 发现这些小分子激活铁调节蛋白1(Irp1)抑制 HIF2A翻译。 在这项应用中，我们建议验证Irp1作为抑制HIF2A在异种移植和 CcRCC和VHL转基因动物模型的建立。此外，我们建议进一步获得 通过识别HIF2A的直接蛋白靶点洞察Irp1-HIF信号的复杂性 抑制剂。最后，我们建议合成一系列hif2a抑制剂的衍生物，以进一步 改善它们的效力和物理化学性质，以产生合适的化合物 用于体内临床前研究和/或进一步体内解剖HIF2A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.