Chemistry, Centre for Chemical Biology, The University of Newcastle , University Drive, Callaghan, New South Wales 2308 Australia.
J Med Chem. 2014 Jan 9;57(1):131-43. doi: 10.1021/jm4015263. Epub 2013 Dec 18.
We reported the first small molecule inhibitors of the interaction between the clathrin N-terminal domain (TD) and endocyctic accessory proteins (i.e., clathrin inhibition1). Initial screening of a ∼17 000 small molecule ChemBioNet library identified 1. Screening of an existing in-house propriety library identified four substituted 1,8-napthalimides as ∼80-120 μM clathrin inhibitors. Focused library development gave 3-sulfo-N-(4-aminobenzyl)-1,8-naphthalimide, potassium salt (18, IC50 ≈ 18 μM). A second library targeting the 4-aminobenzyl moiety was developed, and four analogues displayed comparable activity (26, 27, 28, 34 with IC50 values of 22, 16, 15, and 15 μM respectively) with a further four (24, 25, 32, 33) more active than 18 with IC50 values of 10, 6.9, 12, and 10 μM, respectively. Docking studies rationalized the structure-activity relationship (SAR) with the biological data. 3-Sulfo-N-benzyl-1,8-naphthalimide, potassium salt (25) with an IC50 ≈ 6.9 μM, is the most potent clathrin terminal domain-amphiphysin inhibitor reported to date.
我们报道了第一个能够抑制网格蛋白 N 端结构域（TD）与内吞辅助蛋白相互作用的小分子抑制剂（即网格蛋白抑制物 1）。最初对约 17000 个小分子 ChemBioNet 文库进行了筛选，鉴定出 1 个。对现有的内部专有文库进行筛选，鉴定出 4 个取代的 1,8-萘酰亚胺作为约 80-120 μM 的网格蛋白抑制剂。有针对性的文库开发得到了 3-磺酸-N-（4-氨基苄基）-1,8-萘酰亚胺，钾盐（18，IC50≈18 μM）。针对 4-氨基苄基部分的第二个文库被开发出来，四个类似物显示出相当的活性（26、27、28、34 的 IC50 值分别为 22、16、15 和 15 μM），另外四个（24、25、32、33）比 18 更有效，IC50 值分别为 10、6.9、12 和 10 μM。对接研究用生物数据对结构-活性关系（SAR）进行了合理化解释。3-磺酸-N-苄基-1,8-萘酰亚胺，钾盐（25）的 IC50≈6.9 μM，是迄今为止报道的最有效的网格蛋白末端结构域- amphiphysin 抑制剂。
