Open AccessOff‐target inhibition by active site‐targeting SHP 2 inhibitors
Author(s) -
Tsutsumi Ryouhei,
Ran Hao,
Neel Benjamin G.
Publication year - 2018
Publication title -
febs open bio
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.718
H-Index - 31
ISSN - 2211-5463
DOI - 10.1002/2211-5463.12493
Subject(s) - phosphorylation , phosphatase , mapk/erk pathway , protein tyrosine phosphatase , context (archaeology) , proto oncogene tyrosine protein kinase src , kinase , platelet derived growth factor receptor , tyrosine kinase , microbiology and biotechnology , chemistry , receptor tyrosine kinase , in vitro , growth factor , ligand (biochemistry) , cancer research , biology , biochemistry , signal transduction , receptor , paleontology
Due to the involvement of SHP 2 ( SH 2 domain‐containing protein‐tyrosine phosphatase) in human disease, including Noonan syndrome and cancer, several inhibitors targeting SHP 2 have been developed. Here, we report that the commonly used SHP 2 inhibitor NSC ‐87877 does not exhibit robust inhibitory effects on growth factor‐dependent MAPK (mitogen‐activated protein kinase) pathway activation and that the recently developed active site‐targeting SHP 2 inhibitors IIB ‐08, 11a‐1, and GS ‐493 show off‐target effects on ligand‐evoked activation/trans‐phosphorylation of the PDGFR β (platelet‐derived growth factor receptor β). GS ‐493 also inhibits purified human PDGFR β and SRC in vitro , whereas PDGFR β inhibition by IIB ‐08 and 11a‐1 occurs only in the cellular context. Our results argue for extreme caution in inferring specific functions for SHP 2 based on studies using these inhibitors.