RXDX-106 inhibits TAM and c-MET phosphorylation in vitro. This inhibition of TAM and c-MET activation in vitro is accompanied by a decrease in downstream MAPK andPI3K signaling and cell viability. It completely inhibits cellular proliferation and viability at sub-nanomolar concentrations in TAM-expressing cells.
CEP-40783 is a robust, selective, and orally bioavailable antagonist of AXL and c-Met, exhibiting IC50 values of 7 nM and 12 nM, respectively. In cells transfected with AXL, such as 293GT, CEP-40783's activity is enhanced 27 times more than that of the recombinant enzyme, with an IC50 of 0.26 nM. Additionally, CEP-40783's efficacy against c-Met is pronounced in GTL-16 cells, with an IC50 of 6 nM. This heightened activity in cellular environments may be due to CEP-40783's prolonged binding to AXL and c-Met, aligning with a Type II mechanism. Furthermore, CEP-40783 is highly selective within the kinome, inhibiting over 90% of 298 kinases at a concentration of 1 µM, as indicated by an S90 value of 0.04[1].
CEP-40783 动物研究
Animal study
CEP-40783 demonstrates a dose-responsive and temporal inhibition of AXL phosphorylation in NCI-H1299 NSCL xenografts, achieving 80% inhibition at a dosage of 0.3 mg/kg six hours after administration. At a dosage of 1 mg/kg, it maintains >90% inhibition from 6 to 24 hours post-dose, and a 10 mg/kg oral dose sustains complete AXL inhibition for up to 48 hours post-dosing[1].
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