Stapled α-helical peptide drug development: A potent dual inhibitor of MDM2 and MDMX for p53-dependent cancer therapy
Stapled α-helical peptide drug development: A potent dual inhibitor of MDM2 and MDMX for p53-dependent cancer therapy
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DOI：
10.1073/pnas.1303002110
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发表时间：
2013-09-03
影响因子：
11.1
通讯作者：
Sawyer, Tomi K.
中科院分区：
文献类型：
--
作者：
Chang, Yong S.;Graves, Bradford;Sawyer, Tomi K.
钉接α -螺旋肽已成为一种有前途的新模式，广泛的治疗靶点。在这里，我们报道了一种有效的、选择性的MDM2和MDMX双重抑制剂ATSP-7041，它在体内和体外有效地激活肿瘤中的p53通路。具体而言，ATSP-7041结合MDM2和MDMX具有纳摩尔亲和力，在血清存在的情况下在癌细胞株中显示亚微摩尔细胞活性，并表现出高度特异性的靶向作用机制。高分辨率（1.7埃）x射线晶体结构揭示了其与靶蛋白MDMX的分子相互作用，包括与关键氨基酸的多次接触以及碳氢化合物短纤维本身在靶蛋白结合中的作用。最重要的是，ATSP-7041在MDM2/ mdmx过表达的异种移植肿瘤模型中表现出强大的p53依赖性肿瘤生长抑制作用，与靶药效学活性高度相关，具有良好的药代动力学和组织分布特性。总的来说，ATSP-7041在体外和体内证明了钉钉肽可以作为蛋白质-蛋白质相互作用的治疗相关抑制剂，并可能为癌症治疗提供一种可行的方式。
Stapled alpha-helical peptides have emerged as a promising new modality for a wide range of therapeutic targets. Here, we report a potent and selective dual inhibitor of MDM2 and MDMX, ATSP-7041, which effectively activates the p53 pathway in tumors in vitro and in vivo. Specifically, ATSP-7041 binds both MDM2 and MDMX with nanomolar affinities, shows submicromolar cellular activities in cancer cell lines in the presence of serum, and demonstrates highly specific, on-target mechanism of action. A high resolution (1.7-angstrom) X-ray crystal structure reveals its molecular interactions with the target protein MDMX, including multiple contacts with key amino acids as well as a role for the hydrocarbon staple itself in target engagement. Most importantly, ATSP-7041 demonstrates robust p53-dependent tumor growth suppression in MDM2/MDMX-overexpressing xenograft cancer models, with a high correlation to on-target pharmacodynamic activity, and possesses favorable pharmacokinetic and tissue distribution properties. Overall, ATSP-7041 demonstrates in vitro and in vivo proof-of-concept that stapled peptides can be developed as therapeutically relevant inhibitors of protein-protein interaction and may offer a viable modality for cancer therapy.