Identification of demethylincisterol A 3 as a selective inhibitor of protein tyrosine phosphatase Shp2

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