Discovery of thalidomide-based PROTAC small molecules as the highly efficient SHP2 degraders

• DOI: 10.1016/j.ejmech.2021.113341
• Publication Date: 2021-03-12T05:51:11Z
• Authors: Xiangbo Yang; Zhijia Wang; Yuan Pei; Ning Song; Lei Xu; Bo Feng; Hanlin Wang; Xiaomin Luo; Xiaobei Hu; Xiaohui Qiu; Huijin Feng; Yaxi Yang; Yubo Zhou; Jia Li; Bing Zhou
• Keywords: Proteolysis; Protein Degradation

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 DC50 of 6.02 nM. Further mechanism investigation illustrated that 11 came into function through targeted SHP2 protein degradation.