Identification and Characterization of the First Small Molecule Inhibitor of MDMX
Identification and Characterization of the First Small Molecule Inhibitor of MDMX
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DOI：
10.1074/jbc.m109.056747
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发表时间：
2010-04-02
影响因子：
4.8
通讯作者：
Dyer, Michael A.
中科院分区：
文献类型：
--
作者：
Reed, Damon;Shen, Ying;Dyer, Michael A.
p53通路在几乎所有人类肿瘤中都被破坏。在类似于50%的人类癌症中，p53基因发生突变，而在其余的癌症中，该途径因调节p53途径的其他基因中的遗传病变而失调。表达野生型p53的肿瘤中p53途径失活的一种常见机制是MDM 2或MDMX的表达增加。MDM 2和MDMX通过不同的非冗余机制结合p53并抑制其功能。已经开发了小分子抑制剂和小肽，其在p53结合口袋中结合MDM 2并置换p53蛋白，导致p53介导的细胞周期退出和凋亡。迄今为止，已经开发了MDMX的肽抑制剂，但尚未报道小分子抑制剂。我们已经开发了用于高通量筛选化学文库以鉴定MDMX抑制剂的生物化学和基于细胞的测定，并鉴定了第一个MDMX抑制剂SJ-172550。该化合物可逆地结合MDMX并有效地杀死其中MDMX表达被扩增的视网膜母细胞瘤细胞。SJ-172550与MDM 2抑制剂联合使用时的效果是累加的。一系列生物化学和结构建模研究的结果表明，SJ-172550结合MDMX的p53结合口袋，从而取代p53。这种先导化合物是一种有用的化学支架，用于进一步优化MDMX抑制剂，最终可用于治疗过表达MDMX或具有类似遗传病变的儿科癌症和各种成人肿瘤。当与选择性MDM 2抑制剂组合时，SJ-172550也可用于治疗表达野生型p53的肿瘤。
The p53 pathway is disrupted in virtually every human tumor. In similar to 50% of human cancers, the p53 gene is mutated, and in the remaining cancers, the pathway is dysregulated by genetic lesions in other genes that modulate the p53 pathway. One common mechanism for inactivation of the p53 pathway in tumors that express wild-type p53 is increased expression of MDM2 or MDMX. MDM2 and MDMX bind p53 and inhibit its function by distinct nonredundant mechanisms. Small molecule inhibitors and small peptides have been developed that bind MDM2 in the p53-binding pocket and displace the p53 protein, leading to p53-mediated cell cycle exit and apoptosis. To date, peptide inhibitors of MDMX have been developed, but no small molecule inhibitors have been reported. We have developed biochemical and cell-based assays for high throughput screening of chemical libraries to identify MDMX inhibitors and identified the first MDMX inhibitor SJ-172550. This compound binds reversibly to MDMX and effectively kills retinoblastoma cells in which the expression of MDMX is amplified. The effect of SJ-172550 is additive when combined with an MDM2 inhibitor. Results from a series of biochemical and structural modeling studies suggest that SJ-172550 binds the p53-binding pocket of MDMX, thereby displacing p53. This lead compound is a useful chemical scaffold for further optimization of MDMX inhibitors that may eventually be used to treat pediatric cancers and various adult tumors that overexpress MDMX or have similar genetic lesions. When combined with selective MDM2 inhibitors, SJ-172550 may also be useful for treating tumors that express wild-type p53.