p53 是一种肿瘤抑制蛋白，在细胞周期、细胞凋亡和 DNA 损伤修复的调节中发挥着至关重要的作用。 p53 的降解主要由鼠双分钟 2 (MDM2) 蛋白（一种泛素 E3 连接酶）控制。 MDM2 的过度表达或扩增常见于携带野生型 p53 等位基因的各种人类癌症中，导致 p53 蛋白快速降解和 p53 肿瘤抑制功能减弱。因此，基于 p53 的癌症治疗的主要工作是研究特异性稳定和激活 p53 的 MDM2 拮抗剂，从而抑制肿瘤生长。然而，尽管为开发 MDM2 拮抗剂付出了许多努力，但迄今为止它们仍未能达到临床应用，这主要是因为这些小分子具有细胞毒性。本研究使用我们新设计的基于结构的虚拟筛选方法对商业化合物库进行鉴定，以鉴定一种新化合物 CGMA-Q18，它直接与 MDM2 结合，导致 p53 激活、诱导细胞凋亡和细胞周期停滞。癌细胞。值得注意的是，CGMA-Q18 显着抑制裸鼠体内肿瘤异种移植物的生长，且没有观察到毒性。这些发现强调了我们有用的虚拟筛选方案和 CGMA-Q18 作为假定的 MDM2 拮抗剂。© 2024。作者获得中国科学院上海药物研究所和中国药理学会的独家许可。

p53, a tumor suppressor protein, has a vital role in the regulation of the cell cycle, apoptosis, and DNA damage repair. The degradation of p53 is predominantly controlled by the murine double minute 2 (MDM2) protein, a ubiquitin E3 ligase. The overexpression or amplification of MDM2 is commonly observed in various human cancers bearing wild-type p53 alleles, leading to the rapid degradation of the p53 protein and the attenuation of p53 tumor suppression functions. Thus, a major effort in p53-based cancer therapy has been to research MDM2 antagonists that specifically stabilize and activate p53, leading to the suppression of tumor growth. However, despite numerous efforts to develop MDM2 antagonists, to date they have failed to reach clinical use, largely because of the cytotoxicity associated with these small molecules. This study used our newly designed structure-based virtual screening approach on a commercial compound library to identify a novel compound, CGMA-Q18, which directly binds to MDM2, leading to the activation of p53, the induction of apoptosis, and cell cycle arrest in cancer cells. Notably, CGMA-Q18 significantly inhibited tumor xenograft growth in nude mice without observable toxicity. These findings highlight our useful virtual screening protocol and CGMA-Q18 as a putative MDM2 antagonist.© 2024. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.