开发 HIF-2α 转录因子 PAS-B 结构域抑制剂。
Development of inhibitors of the PAS-B domain of the HIF-2α transcription factor.
机构信息
Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9038, United States.
出版信息
J Med Chem. 2013 Feb 28;56(4):1739-47. doi: 10.1021/jm301847z. Epub 2013 Feb 18.
Abstract
Hypoxia inducible factors (HIFs) are heterodimeric transcription factors induced in a variety of pathophysiological settings, including cancer. We describe the first detailed structure-activity relationship study of small molecules designed to inhibit HIF-2α-ARNT heterodimerization by binding an internal cavity of the HIF-2α PAS-B domain. Through a series of biophysical characterizations of inhibitor-protein interactions (NMR and X-ray crystallography), we have established the structural requirements for artificial inhibitors of the HIF-2α-ARNT PAS-B interaction. These results may serve as a foundation for discovering therapeutic agents that function by a novel mode of action.
摘要
缺氧诱导因子 (HIFs) 是在多种病理生理情况下诱导的异二聚体转录因子，包括癌症。我们描述了第一个小分子结构活性关系研究，这些小分子旨在通过结合 HIF-2α PAS-B 结构域的内部腔来抑制 HIF-2α-ARNT 异二聚化。通过一系列抑制剂-蛋白相互作用的生物物理特性研究（NMR 和 X 射线晶体学），我们确定了人工抑制剂与 HIF-2α-ARNT PAS-B 相互作用的结构要求。这些结果可能为发现通过新型作用模式发挥作用的治疗剂提供基础。
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