Vassilev Lyubomir T, Vu Binh T, Graves Bradford, Carvajal Daisy, Podlaski Frank, Filipovic Zoran, Kong Norman, Kammlott Ursula, Lukacs Christine, Klein Christian, Fotouhi Nader, Liu Emily A
Department of Discovery Oncology, Roche Research Center, Hoffmann-La Roche, Inc., Nutley, NJ 07110, USA.
Science. 2004 Feb 6;303(5659):844-8. doi: 10.1126/science.1092472. Epub 2004 Jan 2.
MDM2 binds the p53 tumor suppressor protein with high affinity and negatively modulates its transcriptional activity and stability. Overexpression of MDM2, found in many human tumors, effectively impairs p53 function. Inhibition of MDM2-p53 interaction can stabilize p53 and may offer a novel strategy for cancer therapy. Here, we identify potent and selective small-molecule antagonists of MDM2 and confirm their mode of action through the crystal structures of complexes. These compounds bind MDM2 in the p53-binding pocket and activate the p53 pathway in cancer cells, leading to cell cycle arrest, apoptosis, and growth inhibition of human tumor xenografts in nude mice.
MDM2与p53肿瘤抑制蛋白具有高亲和力结合，并对其转录活性和稳定性进行负调控。在许多人类肿瘤中发现的MDM2过表达会有效损害p53功能。抑制MDM2与p53的相互作用可以稳定p53，并可能为癌症治疗提供一种新策略。在此，我们鉴定出了高效且选择性的MDM2小分子拮抗剂，并通过复合物的晶体结构证实了它们的作用模式。这些化合物在p53结合口袋中与MDM2结合，并激活癌细胞中的p53通路，导致细胞周期停滞、凋亡以及裸鼠体内人肿瘤异种移植瘤的生长抑制。
