Isoform-Selective and Stereoselective Inhibition of Hypoxia Inducible Factor-2
Isoform-Selective and Stereoselective Inhibition of Hypoxia Inducible Factor-2
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DOI：
10.1021/acs.jmedchem.5b00529
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发表时间：
2015-08-13
影响因子：
7.3
通讯作者：
Tambar, Uttam K.
中科院分区：
文献类型：
--
作者：
Scheuerrnann, Thomas H.;Stroud, Daniel;Tambar, Uttam K.
缺氧诱导因子（HIF）转录因子位于哺乳动物细胞用于感知和响应低氧水平的信号传导途径的中心。虽然对维持氧稳态至关重要，但HIF蛋白活性的失调与肿瘤的发展和转移相关。为了提供靶向失调的HIF活性的人工途径，我们鉴定了HIF-2转录因子的小分子拮抗剂，其结合HIF-2 α亚基的C-末端PAS结构域内的内腔。在这里，我们描述了一类新的手性小分子配体，提供最高的亲和力结合，最有效的，异构体选择性抑制细胞中的HIP-2，并引发迄今为止报道的最大的蛋白质构象变化。目前的结果进一步阐明了HIF-2拮抗作用的分子机制，并提出了开发更高亲和力和效力的HIF-2拮抗剂的其他途径。
Hypoxia inducible factor (HIF) transcription factors reside at the center of signaling pathways used by mammalian cells to sense and respond to low oxygen levels. While essential to maintain oxygen homeostasis, misregulation of HIF protein activity correlates with tumor development and metastasis. To provide artificial routes to target misregulated HIF activity, we identified small molecule antagonists of the HIF-2 transcription factor that bind an internal cavity within the C-terminal PAS domain of the HIF-2 alpha subunit. Here we describe a new class of chiral small molecule ligands that provide the highest affinity binding, the most effective, isoform-selective inhibition of HIP-2 in cells, and trigger the largest protein conformation changes reported to date. The current results further illuminate the molecular mechanism of HIF-2 antagonism and suggest additional routes to develop higher affinity and potency HIF-2 antagonists.