肟酯作为丝氨酸水解酶视网膜母细胞瘤结合蛋白 9（RBBP9）的选择性、共价抑制剂。
Oxime esters as selective, covalent inhibitors of the serine hydrolase retinoblastoma-binding protein 9 (RBBP9).
机构信息
Department of Chemical Physiology, The Scripps Research Institute, 10550 N. Torrey Pines Rd. La Jolla, CA 92037, United States.
出版信息
Bioorg Med Chem Lett. 2010 Apr 1;20(7):2254-8. doi: 10.1016/j.bmcl.2010.02.011. Epub 2010 Feb 6.
Abstract
We recently described a fluorescence polarization platform for competitive activity-based protein profiling (fluopol-ABPP) that enables high-throughput inhibitor screening for enzymes with poorly characterized biochemical activity. Here, we report the discovery of a class of oxime ester inhibitors for the unannotated serine hydrolase RBBP9 from a full-deck (200,000+ compound) fluopol-ABPP screen conducted in collaboration with the Molecular Libraries Screening Center Network (MLSCN). We show that these compounds covalently inhibit RBBP9 by modifying enzyme's active site serine nucleophile and, based on competitive ABPP in cell and tissue proteomes, are selective for RBBP9 relative to other mammalian serine hydrolases.
摘要
我们最近描述了一种用于竞争性基于活性的蛋白质组学（fluopol-ABPP）的荧光偏振平台，该平台可实现对生化活性特征较差的酶的高通量抑制剂筛选。在这里，我们报告了从与分子文库筛选中心网络（MLSCN）合作进行的全面（200,000 多种化合物）fluopol-ABPP 筛选中发现了一类肟酯抑制剂，用于未注释的丝氨酸水解酶 RBBP9。我们表明，这些化合物通过修饰酶的活性位点丝氨酸亲核试剂来共价抑制 RBBP9，并且基于细胞和组织蛋白质组中的竞争性 ABPP，相对于其他哺乳动物丝氨酸水解酶，它们对 RBBP9 具有选择性。
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