Chalcone derivatives antagonize interactions between the human oncoprotein MDM2 and p53
Chalcone derivatives antagonize interactions between the human oncoprotein MDM2 and p53
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DOI：
10.1021/bi000930v
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发表时间：
2001-01-16
期刊：
影响因子：
2.9
通讯作者：
Holak, TA
中科院分区：
文献类型：
--
作者：
Stoll, R;Renner, C;Holak, TA
癌蛋白MDM 2通过与p53反式激活结构域结合来抑制肿瘤抑制蛋白p53。在许多人类肿瘤中，p53基因通过突变或与致癌蛋白结合而失活。在一些肿瘤中，如软组织肉瘤，MDM 2的过表达使原本完整的p53失活，使基因组完整性检查点失效并允许缺陷细胞的细胞周期进展。MDM 2/p53相互作用的破坏导致增加的p53水平和恢复的p53转录活性，表明MDM 2/p53结合拮抗剂的基因组完整性检查和治疗潜力的恢复。在这里，我们通过多维NMR光谱表明，查耳酮（1，3-二苯基-2-丙烯-1-酮）是MDM 2抑制剂，结合到人MDM 2的p53结合裂缝的亚位点。生物化学实验表明，这些化合物可以破坏MDM 2/p53蛋白复合物，从p53/MDM 2和DNA结合的p53/MDM 2复合物中释放p53。因此，这些结果为基于结构的癌症治疗药物设计提供了基础。
The oncoprotein MDM2 inhibits the tumor suppressor protein p53 by binding to the p53 transactivation domain. The p53 gene is inactivated in many human tumors either by mutations or by binding to oncogenic proteins. In some tumors, such as soft tissue sarcomas, overexpression of MDM2 inactivates an otherwise intact p53, disabling the genome integrity checkpoint and allowing cell cycle progression of defective cells. Disruption of the MDM2/p53 interaction leads to increased p53 levels and restored p53 transcriptional activity, indicating restoration of the genome integrity check and therapeutic potential for MDM2/p53 binding antagonists. Here, we show by multidimensional NMR spectroscopy that chalcones (1,3-diphenyl-2-propen-1-ones) are MDM2 inhibitors that bind to a subsite of the p53 binding cleft of human MDM2. Biochemical experiments showed that these compounds can disrupt the MDM2/p53 protein complex, releasing p53 from both the p53/MDM2 and DNA-bound p53/MDM2 complexes. These results thus offer a starting basis for structure-based drug design of cancer therapeutics.