A Method For Overcoming Plasma Protein Inhibition Of Tyrosine Kinase Inhibitors

FMS-like tyrosine kinase 3 (FLT3) is the most frequently mutated gene in acute myeloid leukemia and a target for tyrosine kinase inhibitors (TKI). FLT3 TKIs have yielded limited improvements to clinical outcomes. One reason for this is TKI inhibition by endogenous factors. We characterized plasma protein binding of FLT3 TKI, specifically staurosporine derivatives (STS-TKI) by alpha-1-acid glycoprotein (AGP), simulating its effects upon drug efficacy. Human AGP inhibits the antiproliferative activity of STS-TKI in FLT3/ITD-dependent cells, with IC50 shifts higher than clinically achievable. This is not seen with nonhuman plasma. Mifepristone cotreatment, with its higher AGP affinity, improves TKI activity despite AGP, yielding IC(50)s predicted to be clinically effective. In a mouse model of AGP drug inhibition, mifepristone restores midostaurin activity. This suggests combinatorial methods for overcoming plasma protein inhibition of existing TKIs for leukemia as well as providing a platform for investigating the drug-protein interaction space for developing more potent small-molecule agents.SIGNIFICANCE: Our data provide a mechanism for the failure of some previous TKI clinical trials. The ability of mifepristone to disinhibit TKIs suggests an approach by which the combination of TKIs with already approved and well-tolerated drugs may restore TKI activity.