Off-target inhibition by active site-targeting SHP2 inhibitors

Ryouhei Tsutsumi, Hao Ran, Benjamin G. Neel

Research output: Contribution to journalArticlepeer-review

16 Citations (Scopus)

Abstract

Due to the involvement of SHP2 (SH2 domain-containing protein-tyrosine phosphatase) in human disease, including Noonan syndrome and cancer, several inhibitors targeting SHP2 have been developed. Here, we report that the commonly used SHP2 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 SHP2 inhibitors IIB-08, 11a-1, and GS-493 show off-target effects on ligand-evoked activation/trans-phosphorylation of the PDGFRβ (platelet-derived growth factor receptor β). GS-493 also inhibits purified human PDGFRβ and SRC in vitro, whereas PDGFRβ inhibition by IIB-08 and 11a-1 occurs only in the cellular context. Our results argue for extreme caution in inferring specific functions for SHP2 based on studies using these inhibitors.

Original languageEnglish
Pages (from-to)1405-1411
Number of pages7
JournalFEBS Open Bio
Volume8
Issue number9
DOIs
Publication statusPublished - 2018 Sep

Keywords

  • 11a-1
  • GS-493
  • IIB-08
  • NSC-87877
  • PDGFRβ
  • SHP2 inhibitor

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Fingerprint Dive into the research topics of 'Off-target inhibition by active site-targeting SHP2 inhibitors'. Together they form a unique fingerprint.

Cite this