Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China.
Center of Clinical Oncology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China.
Mol Med. 2022 Sep 7;28(1):109. doi: 10.1186/s10020-022-00537-x.
Targeting ribosome biogenesis to activate p53 has recently emerged as a therapeutic strategy in human cancer. Among various ribosomal proteins, RPL11 centralizes the nucleolar stress-sensing pathway by binding MDM2, leading to MDM2 inactivation and p53 activation. Therefore, the identification of MDM2-binding RPL11-mimetics would be valuable for anti-cancer therapeutics.
Based on the crystal structure of the interface between RPL11 and MDM2, we have identified 15 potential allosteric modulators of MDM2 through the virtual screening.
One of these compounds, named S9, directly binds MDM2 and competitively inhibits the interaction between RPL11 and MDM2, leading to p53 stabilization and activation. Moreover, S9 inhibits cancer cell proliferation in vitro and in vivo. Mechanistic study reveals that MDM2 is required for S9-induced G2 cell cycle arrest and apoptosis, whereas p53 contributes to S9-induced apoptosis.
Putting together, S9 may serve as a lead compound for the development of an anticancer drug that specifically targets RPL11-MDM2-p53 pathway.
靶向核糖体生物发生以激活 p53 最近已成为人类癌症的一种治疗策略。在各种核糖体蛋白中，RPL11 通过与 MDM2 结合，集中核仁应激感应途径，导致 MDM2 失活和 p53 激活。因此，鉴定与 MDM2 结合的 RPL11 模拟物对于抗癌治疗将是有价值的。
基于 RPL11 和 MDM2 之间界面的晶体结构，我们通过虚拟筛选鉴定了 15 种潜在的 MDM2 别构调节剂。
其中一种名为 S9 的化合物可直接与 MDM2 结合并竞争性抑制 RPL11 与 MDM2 之间的相互作用，导致 p53 稳定和激活。此外，S9 在体外和体内抑制癌细胞增殖。机制研究表明，MDM2 是 S9 诱导的 G2 细胞周期阻滞和细胞凋亡所必需的，而 p53 则有助于 S9 诱导的细胞凋亡。
综上所述，S9 可作为一种针对 RPL11-MDM2-p53 通路的抗癌药物的先导化合物。
