USP7 is one of the most studied deubiquitinating enzymes, which is involved in the regulation of multiple cell signaling pathways and has been shown to be associated with the occurrence and progression of a variety of cancers. Inhibitors targeting USP7 have been studied by several teams, but most of them lack selectivity and have low activities. Herein, we reported a serious of pyrrole[2,3-]pyrimidin-4-one derivatives through scaffold hopping of recently reported 4-hydroxypiperidine compounds. The representative compound () exhibited highly potent USP7 inhibition activity as well as anti-proliferative activity against four kinds of cancer cell lines. Further study revealed that effectively inhibited the downstream USP7 pathway and resulted in the accumulation of both p53 and p21 in a dose-dependent manner. Notably, disrupted cell cycle progression through restricting G1 phase and induced significant apoptosis in CHP-212 cells. In summary, our efforts provided a series of novel pyrrole[2,3-]pyrimidin-4-one analogs as potent USP7 inhibitors with excellent anti-cancer activity.

中文翻译：

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发现吡咯并[2,3-d]嘧啶-4-酮衍生物YCH3124作为有效的USP7抑制剂用于癌症治疗


USP7是研究最多的去泛素化酶之一，参与多种细胞信号通路的调节，并已被证明与多种癌症的发生和进展有关。多个团队已经研究了针对 USP7 的抑制剂，但大多数缺乏选择性且活性较低。在此，我们通过最近报道的 4-羟基哌啶化合物的支架跳跃报道了一系列吡咯[2,3-]嘧啶-4-酮衍生物。代表性化合物()对四种癌细胞系表现出高效的USP7抑制活性和抗增殖活性。进一步研究表明，有效抑制下游 USP7 通路，并导致 p53 和 p21 以剂量依赖性方式积累。值得注意的是，通过限制 G1 期扰乱细胞周期进程并诱导 CHP-212 细胞显着凋亡。总之，我们的努力提供了一系列新型吡咯[2,3-]嘧啶-4-酮类似物作为有效的USP7抑制剂，具有优异的抗癌活性。