Takrouri Khuloud, Chen Ting, Papadopoulos Evangelos, Sahoo Rupam, Kabha Eihab, Chen Han, Cantel Sonia, Wagner Gerhard, Halperin Jose A, Aktas Bertal H, Chorev Michael
Laboratory for Translational Research, Hematology, Brigham and Women's Hospital, Harvard Medical School, 20 Shattuck Street, Thorn 7, Boston, MA 02115, USA.
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, USA.
Eur J Med Chem. 2014 Apr 22;77:361-77. doi: 10.1016/j.ejmech.2014.03.034. Epub 2014 Mar 13.
Protein-protein interactions are critical for regulating the activity of translation initiation factors and multitude of other cellular process, and form the largest block of untapped albeit most challenging targets for drug development. 4EGI-1, (E/Z)-2-(2-(4-(3,4-dichlorophenyl)thiazol-2-yl)hydrazono)-3-(2-nitrophenyl)propanoic acid, is a hit compound discovered in a screening campaign of small molecule libraries as an inhibitor of translation initiation factors eIF4E and eIF4G protein-protein interaction; it inhibits translation initiation in vitro and in vivo. A series of 4EGI-1-derived thiazol-2-yl hydrazones have been designed and synthesized in order to delineate the structural latitude and improve its binding affinity to eIF4E, and increase its potency in inhibiting the eIF4E/eIF4G interaction. Probing a wide range of substituents on both phenyl rings comprising the 3-phenylpropionic acid and 4-phenylthiazolidine moieties in the context of both E- and Z-isomers of 4EGI-1 led to analogs with enhanced binding affinity and translation initiation inhibitory activities.
蛋白质-蛋白质相互作用对于调节翻译起始因子的活性以及众多其他细胞过程至关重要，并且构成了药物开发中尚未开发但最具挑战性的最大靶点群。4EGI-1，即（E/Z）-2-（2-（4-（3,4-二氯苯基）噻唑-2-基）腙基）-3-（2-硝基苯基）丙酸，是在小分子文库筛选活动中发现的一种命中化合物，作为翻译起始因子eIF4E和eIF4G蛋白质-蛋白质相互作用的抑制剂；它在体外和体内均抑制翻译起始。为了确定结构范围并提高其与eIF4E的结合亲和力，以及增强其抑制eIF4E/eIF4G相互作用的效力，已经设计并合成了一系列源自4EGI-1的噻唑-2-基腙。在4EGI-1的E-异构体和Z-异构体的背景下，对包含3-苯基丙酸和4-苯基噻唑烷部分的两个苯环上的多种取代基进行探索，得到了具有增强的结合亲和力和翻译起始抑制活性的类似物。
