PDF(Pubmed)
Abstract：
Src homology 2 domain-containing phosphatase 2 (SHP2) is an attractive target for cancer therapy due to its multifaceted roles in both tumor and immune cells. Herein, we designed and synthesized a novel series of proteolysis targeting chimeras (PROTACs) using a SHP2 allosteric inhibitor as warhead, with the goal of achieving SHP2 degradation both inside the cell and in vivo. Among these molecules, compound P9 induces efficient degradation of SHP2 (DC50 = 35.2 ± 1.5 nM) in a concentration- and time-dependent manner. Mechanistic investigation illustrates that the P9-mediated SHP2 degradation requires the recruitment of the E3 ligase and is ubiquitination- and proteasome-dependent. P9 shows improved anti-tumor activity in a number of cancer cell lines over its parent allosteric inhibitor. Importantly, administration of P9 leads to a nearly complete tumor regression in a xenograft mouse model, as a result of robust SHP2 depletion and suppression of phospho-ERK1/2 in the tumor. Hence, P9 represents the first SHP2 PROTAC molecule with excellent in vivo efficacy. It is anticipated that P9 could serve not only as a new chemical tool to interrogate SHP2 biology but also as a starting point for the development of novel therapeutics targeting SHP2.
摘要：
含有Src同源性2结构域的磷酸酶2（SHP2）由于其在肿瘤和免疫细胞中的多方面作用而成为癌症治疗的有吸引力的靶标。在这里，我们设计并合成了一系列新型的蛋白水解靶向嵌合体（PROTACs），使用SHP2变构抑制剂作为弹头，目的是在细胞内和体内实现SHP2降解。在这些分子中，化合物P9以浓度和时间依赖性方式诱导SHP2的有效降解(DC50=35.2±1.5nM)。机制研究表明，P9介导的SHP2降解需要E3连接酶的募集，并且是泛素化和蛋白酶体依赖性的。P9显示在许多癌细胞系中的抗肿瘤活性优于其亲本变构抑制剂。重要的是,在异种移植小鼠模型中，P9的施用导致几乎完全的肿瘤消退，作为肿瘤中SHP2强耗竭和磷酸化ERK1/2抑制的结果。因此，P9代表具有优异体内功效的第一SHP2PROTAC分子。预计P9不仅可以用作询问SHP2生物学的新化学工具，而且可以用作开发靶向SHP2的新疗法的起点。
