State Key Laboratory of Drug Research, Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China; University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing 100049, China.
State Key Laboratory of Drug Research, Cancer Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai, 201203, China.
Eur J Med Chem. 2024 Nov 5;277:116752. doi: 10.1016/j.ejmech.2024.116752. Epub 2024 Aug 5.
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-d]pyrimidin-4-one derivatives through scaffold hopping of recently reported 4-hydroxypiperidine compounds. The representative compound Z33 (YCH3124) exhibited highly potent USP7 inhibition activity as well as anti-proliferative activity against four kinds of cancer cell lines. Further study revealed that YCH3124 effectively inhibited the downstream USP7 pathway and resulted in the accumulation of both p53 and p21 in a dose-dependent manner. Notably, YCH3124 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-d]pyrimidin-4-one analogs as potent USP7 inhibitors with excellent anti-cancer activity.
USP7 是研究最多的去泛素化酶之一，它参与多个细胞信号通路的调节，并且已经被证明与多种癌症的发生和进展有关。已经有几个团队研究了针对 USP7 的抑制剂，但大多数抑制剂缺乏选择性且活性较低。在此，我们通过最近报道的 4-羟基哌啶化合物的结构跳跃，报道了一系列吡咯[2,3-d]嘧啶-4-酮衍生物。代表性化合物 Z33（YCH3124）对 USP7 具有高度抑制活性以及对四种癌细胞系的增殖抑制活性。进一步的研究表明，YCH3124 有效地抑制了下游 USP7 途径，并以剂量依赖性方式导致 p53 和 p21 的积累。值得注意的是，YCH3124 通过限制 G1 期使细胞周期进程受阻，并在 CHP-212 细胞中诱导显著的细胞凋亡。总之，我们的努力提供了一系列新型吡咯[2,3-d]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。
