Discovery of a Novel Shp2 Protein Tyrosine Phosphatase Inhibitor

Abstract

Shp2 is a nonreceptor protein tyrosine phosphatase (PTP) encoded by the PTPN11 gene. It is involved in growth factorinduced activation of mitogen-activated protein (MAP) kinases Erk1 and Erk2 (Erk1/2) and has been implicated in the pathogenicity of the oncogenic bacterium Helicobacter pylori. Moreover, gain-of-function Shp2 mutations have been found in childhood leukemias and Noonan syndrome. Thus, small molecule Shp2 PTP inhibitors are much needed reagents for evaluation of Shp2 as a therapeutic target and for chemical biology studies of Shp2 function. By screening the National Cancer Institute (NCI) Diversity Set chemical library, we identified 8-hydroxy-7-(6-sulfonaphthalen-2-yl)diazenyl-quinoline-5-sulfonic acid (NSC-87877) as a potent Shp2 PTP inhibitor. Molecular modeling and site-directed mutagenesis studies suggested that NSC-87877 binds to the catalytic cleft of Shp2 PTP. NSC-87877 cross-inhibited Shp1 in vitro, but it was selective for Shp2 over other PTPs (PTP1B, HePTP, DEP1, CD45, and LAR). It is noteworthy that NSC-87877 inhibited epidermal growth factor (EGF)-induced activation of Shp2 PTP, Ras, and Erk1/2 in cell cultures but did not block EGF-induced Gab1 tyrosine phosphorylation or Gab1-Shp2 association. Furthermore, NSC-87877 inhibited Erk1/2 activation by a Gab1-Shp2 chimera but did not affect the Shp2-independent Erk1/2 activation by phorbol 12-myristate 13-acetate. These results identified NSC-87877 as the first PTP inhibitor capable of inhibiting Shp2 PTP in cell cultures without a detectable off-target effect. Our study also provides the first pharmacological evidence that Shp2 mediates EGF-induced Erk1/2 MAP kinase activation.

New Approaches to Prevent LEOPARD Syndrome-associated Cardiac Hypertrophy by Specifically Targeting Shp2-dependent Signaling

“…In terms of side effects, Shp2-specific inhibitors may have additional advantages compared with FAK and Akt inhibitors. In the case of the Shp2 inhibitor NSC-87877, it has been shown that the inhibitor preferentially binds Shp2 protein if the gainof-function mutation E76K is present, although the reasons for this are still unclear (37). If PHPS1 also demonstrated preferential binding to mutant Shp2, the possibility of off-target effects would be reduced greatly, but this has not yet been tested.…”

The vitamin K–dependent anticoagulant factor, protein S, inhibits multiple VEGF-A–induced angiogenesis events in a Mer- and SHP2-dependent manner

“…34 Figure 4 shows that ProS inhibited VEGF-Ainduced VEGFR2 tyrosine phosphorylation on Tyr 996 but not Tyr 1175 . As shown in Figure 4, the SHP2 inhibitor NSC 87877 25,35 suppressed the ProS inhibitory effect on VEGFA-induced VEGFR2 phosphorylation. The SHP2 inhibitor NSC 87877 reversed the inhibitory effects of ProS on VEGF-A-induced EC proliferation ( Figure 5A) and MAPK-Erk1/2 ( Figure 5B-C) and Akt activation ( Figure 5D-E).…”

“…Basement membrane matrix (Matrigel) was purchased from BD Biosciences Discovery Labware. NSC87877 SHP 1/2 inhibitor 25 was from Tocris Bioscience. Recombinant human endostatin was from Biopur.…”

Shp2, a novel oncogenic tyrosine phosphatase and potential therapeutic target for human leukemia

“…Inhibition of Shp2 enzymatic activity by overexpression of catalytically inactive Shp2 mutant did not destabilize p210 but enhanced serum starvation-induced apoptosis, suggesting that Shp2 also plays an important role in downstream signaling of the p210 kinase [5]. Interestingly, 8-hydroxy-7-(6-sulfonaphthalen-2-yl) diazenyl-quinoline-5-sulfonic acid (NSC-87877) has been identified as a small molecule with a potent inhibition effect on Shp2 protein-tyrosine phosphatase [10]. NSC-87877 binds to the catalytic cleft of Shp2 and is selective for Shp2 over other protein-tyrosine phosphatases without a detectable off-target effect [10].…”

“…Interestingly, 8-hydroxy-7-(6-sulfonaphthalen-2-yl) diazenyl-quinoline-5-sulfonic acid (NSC-87877) has been identified as a small molecule with a potent inhibition effect on Shp2 protein-tyrosine phosphatase [10]. NSC-87877 binds to the catalytic cleft of Shp2 and is selective for Shp2 over other protein-tyrosine phosphatases without a detectable off-target effect [10].…”