Department of Chemical Science and Technologies, University of Rome Tor Vergata, Rome 00133, Italy.
Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome 00146, Italy.
J Med Chem. 2021 Nov 11;64(21):15973-15990. doi: 10.1021/acs.jmedchem.1c01371. Epub 2021 Oct 29.
We developed a new class of inhibitors of protein-protein interactions of the SHP2 phosphatase, which is pivotal in cell signaling and represents a central target in the therapy of cancer and rare diseases. Currently available SHP2 inhibitors target the catalytic site or an allosteric pocket but lack specificity or are ineffective for disease-associated SHP2 mutants. Considering that pathogenic lesions cause signaling hyperactivation due to increased levels of SHP2 association with cognate proteins, we developed peptide-based molecules with nanomolar affinity for the N-terminal Src homology domain of SHP2, good selectivity, stability to degradation, and an affinity for pathogenic variants of SHP2 that is 2-20 times higher than for the wild-type protein. The best peptide reverted the effects of a pathogenic variant (D61G) in zebrafish embryos. Our results provide a novel route for SHP2-targeted therapies and a tool for investigating the role of protein-protein interactions in the function of SHP2.
我们开发了一类新型 SHP2 磷酸酶蛋白-蛋白相互作用抑制剂，该酶在细胞信号转导中起着关键作用，是癌症和罕见病治疗的一个重要靶点。目前可用的 SHP2 抑制剂针对催化位点或别构口袋，但缺乏特异性或对与疾病相关的 SHP2 突变体无效。鉴于致病病变会因 SHP2 与同源蛋白的结合水平增加而导致信号过度激活，我们开发了基于肽的分子，其对 SHP2 的 N 端Src 同源结构域具有纳摩尔亲和力，具有良好的选择性、对降解的稳定性，并且对 SHP2 的致病性变体的亲和力比野生型蛋白高 2-20 倍。最佳肽可逆转斑马鱼胚胎中致病性变体（D61G）的作用。我们的研究结果为 SHP2 靶向治疗提供了新途径，并为研究蛋白质-蛋白质相互作用在 SHP2 功能中的作用提供了工具。
