Histone lysine specific demethylase 1 (LSD1) has become a potential therapeutic target for the treatment of cancer. Discovery and develop novel and potent LSD1 inhibitors is a challenge, although several of them have already entered into clinical trials. Herein, for the first time, we reported the discovery of a series of 5-cyano-6-phenylpyrimidine derivatives as LSD1 inhibitors using flavin adenine dinucleotide (FAD) similarity-based designing strategy, of which compound 14q was finally identified to repress LSD1 with IC₅₀ = 183 nmol/L. Docking analysis suggested that compound 14q fitted well into the FAD-binding pocket. Further mechanism studies showed that compound 14q may inhibit LSD1 activity competitively by occupying the FAD binding sites of LSD1 and inhibit cell migration and invasion by reversing epithelial to mesenchymal transition (EMT). Overall, these findings showed that compound 14q is a suitable candidate for further development of novel FAD similarity-based LSD1 inhibitors.

组蛋白赖氨酸特异性脱甲基酶1（LSD1）已成为治疗癌症的潜在治疗靶标。发现和开发新型有效的LSD1抑制剂是一项挑战，尽管其中一些已经进入临床试验。在此，我们首次报道了使用基于黄素腺嘌呤二核苷酸（FAD）相似性的设计策略发现了一系列5-氰基-6-苯基嘧啶衍生物作为LSD1抑制剂，最终确定了其中的化合物14q可以抑制LSD1 IC ₅₀  ＝ 183nmol / L。对接分析表明，化合物14q非常适合FAD结合袋。进一步的机理研究表明，化合物14q可能通过占据LSD1的FAD结合位点竞争性抑制LSD1活性，并通过逆转上皮向间质转化（EMT）抑制细胞迁移和侵袭。总体而言，这些发现表明，化合物14q是进一步开发新型基于FAD相似性的LSD1抑制剂的合适候选者。