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

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. (c) 2021 Elsevier Masson SAS. All rights reserved.

Automated summary

SHP2, a non-receptor tyrosine phosphatase, plays a crucial role in various oncogenic cell signaling cascades. PROTAC has emerged as a promising strategy for degrading disease-related proteins. Through the design and evaluation of a series of thalidomide-based heterobifunctional molecules, a highly efficient SHP2 degrader was identified, providing a new strategy for SHP2-mediated cancer therapy.