Deng Xiaobing, Zhang Xiaoling, Tang Bo, Liu Hongbo, Shen Qi, Liu Ying, Lai Luhua
Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China.
Center for Quantitative Biology, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China.
Front Chem. 2018 Apr 4;6:98. doi: 10.3389/fchem.2018.00098. eCollection 2018.
Tumor necrosis factor-α (TNF-α) plays a pivotal role in inflammatory response. Dysregulation of TNF can lead to a variety of disastrous pathological effects, including auto-inflammatory diseases. Antibodies that directly targeting TNF-α have been proven effective in suppressing symptoms of these disorders. Compared to protein drugs, small molecule drugs are normally orally available and less expensive. Till now, peptide and small molecule TNF-α inhibitors are still in the early stage of development, and much more efforts should be made. In a previously study, we reported a TNF-α inhibitor, with modest activity. Here, we optimized this compound by shape screen and rational design. In the first round, we screened commercial compound library for analogs based on shape similarity. Out of the 68 compounds tested, 20 compounds showed better binding affinity than in the SPR competitive binding assay. These 20 compounds were tested in cell assay and the most potent compound was 2-oxo-N-phenyl-1,2-dihydrobenzo[]indole-6-sulfonamide () with an IC of 14 μM, which was 2.2-fold stronger than . Based on the docking analysis of and binding with TNF-α, in the second round, we designed analogs, purchased seven of them, and synthesized seven new compounds. The best compound, showed an IC-value of 3 μM in cell assay, which was 14-fold stronger than . was among the most potent TNF-α organic compound inhibitors reported so far. Our study demonstrated that 2-oxo-N-phenyl-1,2-dihydrobenzo[]indole-6-sulfonamide analogs could be developed as potent TNF-α inhibitors. can be further optimized for its activity and properties. Our study provides insights into designing small molecule inhibitors directly targeting TNF-α and for protein-protein interaction inhibitor design.
肿瘤坏死因子-α（TNF-α）在炎症反应中起关键作用。TNF的失调会导致多种灾难性的病理效应，包括自身炎症性疾病。直接靶向TNF-α的抗体已被证明可有效抑制这些疾病的症状。与蛋白质药物相比，小分子药物通常可口服且成本较低。到目前为止，肽和小分子TNF-α抑制剂仍处于开发的早期阶段，需要付出更多努力。在之前的一项研究中，我们报道了一种活性适中的TNF-α抑制剂。在此，我们通过形状筛选和合理设计对该化合物进行了优化。在第一轮中，我们基于形状相似性筛选了商业化合物库以寻找类似物。在测试的68种化合物中，有20种化合物在表面等离子体共振（SPR）竞争性结合试验中显示出比[原文中提及的某个对比化合物]更好的结合亲和力。这20种化合物在细胞试验中进行了测试，最有效的化合物是2-氧代-N-苯基-1,2-二氢苯并[h]吲哚-6-磺酰胺（[具体化合物名称]），其半数抑制浓度（IC）为14 μM，比[对比化合物]强2.2倍。基于[具体化合物名称]和[对比化合物]与TNF-α结合的对接分析，在第二轮中，我们设计了[具体化合物名称]的类似物，购买了其中七种，并合成了七种新化合物。最佳化合物[具体化合物名称]在细胞试验中的IC值为3 μM，比[对比化合物]强14倍。[具体化合物名称]是迄今为止报道的最有效的TNF-α有机化合物抑制剂之一。我们的研究表明，2-氧代-N-苯基-1,2-二氢苯并[h]吲哚-6-磺酰胺类似物可开发为有效的TNF-α抑制剂。[具体化合物名称]的活性和性质可进一步优化。我们的研究为直接靶向TNF-α的小分子抑制剂设计以及蛋白质-蛋白质相互作用抑制剂设计提供了思路。
