Department of Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing, 100049, China.
National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; School of Pharmaceutical Science, Jiangnan University, Wuxi, 214122, China.
Eur J Med Chem. 2021 Jun 5;218:113341. doi: 10.1016/j.ejmech.2021.113341. Epub 2021 Mar 11.
SHP2, a non-receptor tyrosine phosphatase, plays a pivotal role in numerous oncogenic cell-signaling cascades like RAS-ERK, PI3K-AKT and JAK-STAT. On the other hand, proteolysis targeting chimera (PROTAC) has emerged as a promising strategy for the degradation of disease-related protein of interest (POI). SHP2 degradation via the PROTAC strategy will provide an alternative startegy for SHP2-mediated cancer therapy. Herein we described the design, synthesis and evaluation of a series of thalidomide-based heterobifunctional molecules and identified 11(ZB-S-29) as the highly efficient SHP2 degrader with a DC of 6.02 nM. Further mechanism investigation illustrated that 11 came into function through targeted SHP2 protein degradation.
SHP2 是一种非受体酪氨酸磷酸酶，在 RAS-ERK、PI3K-AKT 和 JAK-STAT 等众多致癌细胞信号通路中发挥关键作用。另一方面，蛋白水解靶向嵌合体（PROTAC）已成为降解靶蛋白（POI）的一种很有前途的策略。通过 PROTAC 策略降解 SHP2 将为 SHP2 介导的癌症治疗提供一种替代策略。本文描述了一系列基于沙利度胺的杂双功能分子的设计、合成和评价，并鉴定出 11（ZB-S-29）为高效 SHP2 降解剂，其 DC 为 6.02 nM。进一步的机制研究表明，11 通过靶向 SHP2 蛋白降解发挥作用。
