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, EJMC-1 with modest activity. Here, we optimized this compound by shape screen and rational design. In the first round, we screened commercial compound library for EJMC-1 analogs based on shape similarity. Out of the 68 compounds tested, 20 compounds showed better binding affinity than EJMC-1 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[cd]indole-6-sulfonamide (S10) with an IC50 of 14 μM, which was 2.2-fold stronger than EJMC-1. Based on the docking analysis of S10 and EJMC-1 binding with TNF-α, in the second round, we designed S10 analogs, purchased seven of them, and synthesized seven new compounds. The best compound, 4e showed an IC50-value of 3 μM in cell assay, which was 14-fold stronger than EJMC-1. 4e was among the most potent TNF-α organic compound inhibitors reported so far. Our study demonstrated that 2-oxo-N-phenyl-1,2-dihydrobenzo[cd]indole-6-sulfonamide analogs could be developed as potent TNF-α inhibitors. 4e 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.

中文翻译：

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设计，合成和评价二氢苯并[cd]吲哚-6-磺酰胺作为TNF-α抑制剂。

肿瘤坏死因子-α（TNF-α）在炎症反应中起关键作用。TNF的失调可导致多种灾难性病理影响，包括自身炎症性疾病。已证明直接靶向TNF-α的抗体可有效抑制这些疾病的症状。与蛋白质药物相比，小分子药物通常可以口服且价格便宜。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，应做出更多努力。在先前的研究中，我们报道了具有中等活性的TNF-α抑制剂EJMC-1。在这里，我们通过形状筛选和合理的设计优化了该化合物。在第一轮中，我们根据形状相似性筛选了EJMC-1类似物的商业化合物库。在测试的68种化合物中，在SPR竞争结合试验中，有20种化合物的结合亲和力比EJMC-1好。这20种化合物在细胞分析中进行了测试，最有效的化合物是2-氧代-N-苯基-1,2-二氢苯并[cd]吲哚-6-磺酰胺（S10），IC50为14μM，是2.2倍比EJMC-1强。在第二轮中基于S10和EJMC-1与TNF-α结合的对接分析，我们设计了S10类似物，购买了其中的7个，并合成了7个新化合物。最佳化合物4e在细胞测定中显示出3μM的IC50值，比EJMC-1强14倍。4e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[cd]吲哚-6-磺酰胺类似物可以开发为有效的TNF-α抑制剂。可以针对其活性和特性进一步优化4e。