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 TKI 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 anti-proliferative activity of STS-TKI in FLT3-ITD-dependent cells, with IC ₅₀ shifts higher than clinically achievable. This is not seen with non-human plasma. Mifepristone co-treatment, 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.
Competing Interests: Conflict of Interest The authors report no subject specific conflicts of interest. D.S. does serve on the SAB of InSilico Medicine and receives research support and serves as a consultant for an unrelated project from PHarosI&BT co, Ltd.. D.J.Y. is now the principal investigator on an unrelated trial sponsored by Novartis, begun after his involvement in this work, and does not receive compensation.