Identification of a Structural Determinant for Selective Targeting of HDMX.
Identification of a Structural Determinant for Selective Targeting of HDMX.
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DOI：
10.1016/j.str.2020.04.011
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发表时间：
2020-04
期刊：
影响因子：
5.7
通讯作者：
Y. Ben-Nun;H. Seo;Edward P. Harvey;Zachary J. Hauseman;T. Wales;C. Newman;A. Cathcart;J. Engen;S. Dhe-Paganon;L. Walensky
中科院分区：
文献类型：
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作者：
Y. Ben-Nun;H. Seo;Edward P. Harvey;Zachary J. Hauseman;T. Wales;C. Newman;A. Cathcart;J. Engen;S. Dhe-Paganon;L. Walensky
P53是一种重要的肿瘤抑制蛋白，通过诱导细胞周期阻滞或细胞凋亡来保护人类基因组免受突变。癌细胞通过缺失、突变或过表达负调节因子HDM2和HDMX来破坏p53。对于保留野生型p53的肿瘤，通过药物靶向HDM2和/或HDMX来重新激活它代表了一种很有前途的策略，一系列选择性小分子HDM2抑制剂和双重HDM2/HDMX钉钉肽抑制剂正在临床试验中进行评估。由于选择性HDM2靶向可引起血液学毒性，选择性HDMX抑制剂可提供另一种p53再激活策略，但临床候选药物尚不明确。在这里，我们应用突变扫描方法来揭示基于p53的钉接肽对HDMX具有选择性。钉接肽/HDMX复合物的晶体结构揭示了观察到的特异性的分子机制，并通过HDMX诱变验证了这一点。因此，我们为开发HDMX选择性抑制剂来解剖和靶向p53/HDMX相互作用提供了蓝图。
p53 is a critical tumor-suppressor protein that guards the human genome against mutations by inducing cell-cycle arrest or apoptosis. Cancer cells subvert p53 by deletion, mutation, or overexpression of the negative regulators HDM2 and HDMX. For tumors that retain wild-type p53, its reactivation by pharmacologic targeting of HDM2 and/or HDMX represents a promising strategy, with a series of selective small-molecule HDM2 inhibitors and a dual HDM2/HDMX stapled-peptide inhibitor being evaluated in clinical trials. Because selective HDM2 targeting can cause hematologic toxicity, selective HDMX inhibitors could provide an alternative p53-reactivation strategy, but clinical candidates remain elusive. Here, we applied a mutation-scanning approach to uncover p53-based stapled peptides that are selective for HDMX. Crystal structures of stapled-peptide/HDMX complexes revealed a molecular mechanism for the observed specificity, which was validated by HDMX mutagenesis. Thus, we provide a blueprint for the development of HDMX-selective inhibitors to dissect and target the p53/HDMX interaction.