In vivo activation of the p53 pathway by small-molecule antagonists of MDM2
In vivo activation of the p53 pathway by small-molecule antagonists of MDM2
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DOI：
10.1126/science.1092472
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发表时间：
2004-02-06
期刊：
影响因子：
56.9
通讯作者：
Liu, EA
中科院分区：
文献类型：
--
作者：
Vassilev, LT;Vu, BT;Liu, EA
MDM2以高亲和力结合P53抑癌蛋白，负向调节其转录活性和稳定性。在许多人类肿瘤中发现的MDM2的过度表达，有效地损害了P53的功能。抑制MDM2-P53的相互作用可以稳定P53，并可能为肿瘤治疗提供新的策略。在这里，我们确定了有效的和选择性的MDM2小分子拮抗剂，并通过络合物的晶体结构确定了它们的作用模式。这些化合物结合P53结合口袋中的MDM2并激活癌细胞中的P53途径，导致细胞周期停滞、细胞凋亡和裸鼠人肿瘤移植瘤的生长抑制。
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.