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Target-Mediated Brain Tissue Binding for Small Molecule Inhibitors of Heat Shock Protein 90

Drug distribution in the brain is generally associated with an affinity for fatty brain tissues and therefore known to be species- and concentration-independent. We report here the effect of target affinity on brain tissue binding for 10 small molecules designed to inhibit brain heat shock protein 9...

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Autores principales: Badolo, Lassina, Thirstrup, Kenneth, Nielsen, Søren Møller, Püschl, Ask, Jensen, Thomas, Watson, Steve, Bundgaard, Christoffer
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7690585/
https://www.ncbi.nlm.nih.gov/pubmed/33105895
http://dx.doi.org/10.3390/pharmaceutics12111009
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author Badolo, Lassina
Thirstrup, Kenneth
Nielsen, Søren Møller
Püschl, Ask
Jensen, Thomas
Watson, Steve
Bundgaard, Christoffer
author_facet Badolo, Lassina
Thirstrup, Kenneth
Nielsen, Søren Møller
Püschl, Ask
Jensen, Thomas
Watson, Steve
Bundgaard, Christoffer
author_sort Badolo, Lassina
collection PubMed
description Drug distribution in the brain is generally associated with an affinity for fatty brain tissues and therefore known to be species- and concentration-independent. We report here the effect of target affinity on brain tissue binding for 10 small molecules designed to inhibit brain heat shock protein 90 (HSP90), a widespread protein whose expression is 1–2% of total cytosolic proteins in eucaryotes. Our results show that increasing the test item concentrations from 0.3 to 100 µM increased the unbound fraction 32-fold for the most potent molecules, with no change for the inactive one (1.1 fold change). Saturation of HSP90 led to normal concentration-independent brain tissue binding. In vivo pharmacokinetics performed in rats showed that the overall volume of distribution of compounds is correlated with their affinity for HSP90. The in vitro binding and in vivo pharmacokinetics (PK) performed in rats showed that small molecule HSP90 inhibitors followed the principle of target-mediated drug disposition. We demonstrate that assessing unbound fractions in brain homogenate was subject to HSP90 target interference; this may challenge the process of linking systemic-free drug concentrations to central nervous system unbound concentrations necessary to establish the proper pharmacokinetics/pharmacodynamics (PK/PD) relation needed for human dose prediction.
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spelling pubmed-76905852020-11-27 Target-Mediated Brain Tissue Binding for Small Molecule Inhibitors of Heat Shock Protein 90 Badolo, Lassina Thirstrup, Kenneth Nielsen, Søren Møller Püschl, Ask Jensen, Thomas Watson, Steve Bundgaard, Christoffer Pharmaceutics Article Drug distribution in the brain is generally associated with an affinity for fatty brain tissues and therefore known to be species- and concentration-independent. We report here the effect of target affinity on brain tissue binding for 10 small molecules designed to inhibit brain heat shock protein 90 (HSP90), a widespread protein whose expression is 1–2% of total cytosolic proteins in eucaryotes. Our results show that increasing the test item concentrations from 0.3 to 100 µM increased the unbound fraction 32-fold for the most potent molecules, with no change for the inactive one (1.1 fold change). Saturation of HSP90 led to normal concentration-independent brain tissue binding. In vivo pharmacokinetics performed in rats showed that the overall volume of distribution of compounds is correlated with their affinity for HSP90. The in vitro binding and in vivo pharmacokinetics (PK) performed in rats showed that small molecule HSP90 inhibitors followed the principle of target-mediated drug disposition. We demonstrate that assessing unbound fractions in brain homogenate was subject to HSP90 target interference; this may challenge the process of linking systemic-free drug concentrations to central nervous system unbound concentrations necessary to establish the proper pharmacokinetics/pharmacodynamics (PK/PD) relation needed for human dose prediction. MDPI 2020-10-22 /pmc/articles/PMC7690585/ /pubmed/33105895 http://dx.doi.org/10.3390/pharmaceutics12111009 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Badolo, Lassina
Thirstrup, Kenneth
Nielsen, Søren Møller
Püschl, Ask
Jensen, Thomas
Watson, Steve
Bundgaard, Christoffer
Target-Mediated Brain Tissue Binding for Small Molecule Inhibitors of Heat Shock Protein 90
title Target-Mediated Brain Tissue Binding for Small Molecule Inhibitors of Heat Shock Protein 90
title_full Target-Mediated Brain Tissue Binding for Small Molecule Inhibitors of Heat Shock Protein 90
title_fullStr Target-Mediated Brain Tissue Binding for Small Molecule Inhibitors of Heat Shock Protein 90
title_full_unstemmed Target-Mediated Brain Tissue Binding for Small Molecule Inhibitors of Heat Shock Protein 90
title_short Target-Mediated Brain Tissue Binding for Small Molecule Inhibitors of Heat Shock Protein 90
title_sort target-mediated brain tissue binding for small molecule inhibitors of heat shock protein 90
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7690585/
https://www.ncbi.nlm.nih.gov/pubmed/33105895
http://dx.doi.org/10.3390/pharmaceutics12111009
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