Identification of demethylincisterol A3 as a selective inhibitor of protein tyrosine phosphatase Shp2

Shp2 is a classical non-receptor protein tyrosine phosphatase (PTP) involved in many human diseases such as Noonan syndrome and tumors, and identified as a potential therapeutic target. In order to find a potent and selective Shp2 inhibitor, we screened a diverse collection of the secondary metabolites from endophyte fungi using an in vitro enzyme assay, and finally identified a potent Shp2 inhibitor, HLP46 (demethylincisterol A3) from Pestalotiopsis sp. HLP46 was reported to have anti-tumor and anti-inflammation activity previously. We provide the first evidence that HLP46 is an inhibitor of the Shp2. HLP46 shows high selective inhibition of Shp2 over Shp1, PTP1B, Lyp, STEP, PTPRA and Cdc25b. Enzymatic kinetic analyses showed that HLP46 is a non-competitive inhibitor of Shp2. HLP46 interrupts Gab1-Shp2 association and blocked Shp2-dependent activation of the Ras/ERK signal pathway induced by EGF. Furthermore, HLP46 decreased Src activation and inhibit tumor cell migration and invasion. As expected, HLP46 has no effect on the Shp2-independent activation of ERK induced by PMA or on the activation of the PI3K/Akt pathway. We testified therapeutic efficacy targeting both Shp2 and PI3K in MCF7 cells. HLP46 does not show any synergistic inhibition with PI3K inhibitor in suppressing cell growth. Collectively, these results suggest that HLP46 is a selective Shp2 inhibitor and could inhibit Shp2-dependent cell signaling in human cells.