Roche Research Center, Hoffmann-La Roche Inc., Nutley, NJ 07110, USA.
Curr Top Microbiol Immunol. 2011;348:151-72. doi: 10.1007/82_2010_110.
The p53 tumor suppressor is controlled by MDM2, which binds p53 and negatively regulates its transcriptional activity and stability. Many tumors overproduce MDM2 to impair p53 function. Therefore, restoration of p53 activity by inhibiting the p53-MDM2 binding represents an attractive novel approach to cancer therapy. Recently developed potent and selective small-molecule antagonists of the p53-MDM2 interaction have been used to demonstrate the proof-of-concept for this approach. These compounds interact specifically with the p53-binding pocket of MDM2 and release p53 from negative control. Treatment of cancer cells expressing wild-type p53 stabilize p53 and activate the p53 pathway, leading to cell cycle arrest and apoptosis. In mice-bearing established human tumor xenografts, MDM2 antagonists caused tumor inhibition and regression at nontoxic concentrations, suggesting that they may have a therapeutic utility in the treatment of cancer. An increasing number of MDM2 antagonists are being generated and some of them have entered clinical trials. Here, we review this class of emerging drugs with an emphasis on small molecules that inhibit the p53-MDM2 interaction.
p53 肿瘤抑制因子受 MDM2 控制，MDM2 与 p53 结合并负调控其转录活性和稳定性。许多肿瘤过度产生 MDM2 以损害 p53 功能。因此，通过抑制 p53-MDM2 结合来恢复 p53 活性代表了一种有吸引力的癌症治疗新方法。最近开发的强效和选择性的 p53-MDM2 相互作用小分子拮抗剂已被用于证明该方法的概念验证。这些化合物与 MDM2 的 p53 结合口袋特异性相互作用，并将 p53 从负调控中释放出来。用表达野生型 p53 的癌细胞进行治疗可稳定 p53 并激活 p53 途径，导致细胞周期停滞和细胞凋亡。在携带已建立的人肿瘤异种移植物的小鼠中，MDM2 拮抗剂在非毒性浓度下引起肿瘤抑制和消退，表明它们在癌症治疗中可能具有治疗用途。越来越多的 MDM2 拮抗剂正在被开发出来，其中一些已经进入临床试验。在这里，我们重点介绍抑制 p53-MDM2 相互作用的小分子，对这一类新兴药物进行综述。
