The protein tyrosine phosphatase (PTP) Shp2 (PTPN11) is an attractive target for anticancer drug discovery because it mediates growth factor signaling and its gain-of-function mutants are causally linked to leukemias[3]. SPI-112 is a cell-impermeable and selective inhibitor of Shp2 with an IC50 value of 1 µM in cell-free assays[4]. In SPR binding assay, SPI-112 displayed a 1:1 stoichiometric binding kinetics to Shp2 with a kinetic constant (KD) of 1.30±0.14 µM and the association and dissociation rates of Ka=2.24×104/Ms and KD=0.029/s. Shp2 PTP activity and function were inhibited in cells treated with SPI-112Me, a prodrug of SPI-112, indicating that SPI-112Me is a cell-active Shp2 PTP inhibitor[3].
作用机制
SPI-112 bound to Shp2 by surface plasmon resonance (SPR)[3].
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