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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 pr...

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Autores principales: Young, David J., Nguyen, Bao, Li, Li, Higashimoto, Tomoyasu, Levis, Mark J., Liu, Jun O., Small, Donald
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for Cancer Research 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8478262/
https://www.ncbi.nlm.nih.gov/pubmed/34589716
http://dx.doi.org/10.1158/2643-3230.BCD-20-0119
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author Young, David J.
Nguyen, Bao
Li, Li
Higashimoto, Tomoyasu
Levis, Mark J.
Liu, Jun O.
Small, Donald
author_facet Young, David J.
Nguyen, Bao
Li, Li
Higashimoto, Tomoyasu
Levis, Mark J.
Liu, Jun O.
Small, Donald
author_sort Young, David J.
collection PubMed
description 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 IC(50) 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.
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spelling pubmed-84782622021-09-28 A Method for Overcoming Plasma Protein Inhibition of Tyrosine Kinase Inhibitors Young, David J. Nguyen, Bao Li, Li Higashimoto, Tomoyasu Levis, Mark J. Liu, Jun O. Small, Donald Blood Cancer Discov Research Articles 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 IC(50) 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. American Association for Cancer Research 2021-07-02 /pmc/articles/PMC8478262/ /pubmed/34589716 http://dx.doi.org/10.1158/2643-3230.BCD-20-0119 Text en ©2021 The Authors; Published by the American Association for Cancer Research https://creativecommons.org/licenses/by-nc-nd/4.0/This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs International 4.0 License.
spellingShingle Research Articles
Young, David J.
Nguyen, Bao
Li, Li
Higashimoto, Tomoyasu
Levis, Mark J.
Liu, Jun O.
Small, Donald
A Method for Overcoming Plasma Protein Inhibition of Tyrosine Kinase Inhibitors
title A Method for Overcoming Plasma Protein Inhibition of Tyrosine Kinase Inhibitors
title_full A Method for Overcoming Plasma Protein Inhibition of Tyrosine Kinase Inhibitors
title_fullStr A Method for Overcoming Plasma Protein Inhibition of Tyrosine Kinase Inhibitors
title_full_unstemmed A Method for Overcoming Plasma Protein Inhibition of Tyrosine Kinase Inhibitors
title_short A Method for Overcoming Plasma Protein Inhibition of Tyrosine Kinase Inhibitors
title_sort method for overcoming plasma protein inhibition of tyrosine kinase inhibitors
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8478262/
https://www.ncbi.nlm.nih.gov/pubmed/34589716
http://dx.doi.org/10.1158/2643-3230.BCD-20-0119
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