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Phase 1 and preclinical profiling of ESM‐HDAC391, a myeloid‐targeted histone deacetylase inhibitor, shows enhanced pharmacology and monocytopaenia

AIMS: To improve the tolerability and therapeutic application of histone deacetylase inhibitors (HDACi), by application of an esterase‐sensitive motif (ESM), to target pharmacological activity directly to mononuclear myeloid cells expressing the processing enzyme carboxylesterase‐1 (CES1). METHODS:...

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Autores principales: Furze, Rebecca C., Molnar, Judit, Parr, Nigel J., Ahmad, Faiz, Henry, Yvette, Howe, David, Singh, Rajendra, Toal, Martin, Bassil, Anna K., Bernard, Sharon G., Davis, Robert P., Gibson, Adele, Maller, N. Claire, Sharp, Catriona, Tough, David F., Prinjha, Rab K., Lewis, Huw D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9796293/
https://www.ncbi.nlm.nih.gov/pubmed/35655123
http://dx.doi.org/10.1111/bcp.15428
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author Furze, Rebecca C.
Molnar, Judit
Parr, Nigel J.
Ahmad, Faiz
Henry, Yvette
Howe, David
Singh, Rajendra
Toal, Martin
Bassil, Anna K.
Bernard, Sharon G.
Davis, Robert P.
Gibson, Adele
Maller, N. Claire
Sharp, Catriona
Tough, David F.
Prinjha, Rab K.
Lewis, Huw D.
author_facet Furze, Rebecca C.
Molnar, Judit
Parr, Nigel J.
Ahmad, Faiz
Henry, Yvette
Howe, David
Singh, Rajendra
Toal, Martin
Bassil, Anna K.
Bernard, Sharon G.
Davis, Robert P.
Gibson, Adele
Maller, N. Claire
Sharp, Catriona
Tough, David F.
Prinjha, Rab K.
Lewis, Huw D.
author_sort Furze, Rebecca C.
collection PubMed
description AIMS: To improve the tolerability and therapeutic application of histone deacetylase inhibitors (HDACi), by application of an esterase‐sensitive motif (ESM), to target pharmacological activity directly to mononuclear myeloid cells expressing the processing enzyme carboxylesterase‐1 (CES1). METHODS: This first‐in‐human study comprised single and multiple ascending dose cohorts to determine safety and tolerability. Pharmacodynamic parameters included acetylation, cytokine inhibition and intracellular concentrations of processed acid metabolite in isolated monocytes. Mechanistic work was conducted in vitro and in a CES1/Es1e ( lo ) mouse strain. RESULTS: ESM‐HDAC391 showed transient systemic exposure (plasma half‐life of 21–30 min) but selective retention of processed acid for at least 12 hours, resulting in robust targeted mechanistic engagement (increased acetylation in monocytes plus inhibition of ex vivo stimulated cytokine production). ESM‐HDAC391 was well tolerated and clinical toxicities common to non‐targeted HDACi were not observed. ESM‐HDAC391 treatment was accompanied by the novel finding of a dose‐dependent monocyte depletion that was transient and reversible and which plateaued at 0.06 × 10(9) monocytes/L after repeat dosing with 20 or 40 mg. Characterisation of monocyte depletion in transgenic mice (CES1/Es1e ( lo )) suggested that colony stimulating factor 1 receptor loss on circulating cells contributed to ESM‐HDAC‐mediated depletion. Further mechanistic investigations using human monocytes in vitro demonstrated HDACi‐mediated change in myeloid fate through modulation of colony stimulating factor 1 receptor and downstream effects on cell differentiation. CONCLUSION: These findings demonstrate selective targeting of monocytes in humans using the ESM approach and identify monocytopaenia as a novel outcome of ESM‐HDACi treatment, with implications for potential benefit of these molecules in myeloid‐driven diseases.
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spelling pubmed-97962932022-12-30 Phase 1 and preclinical profiling of ESM‐HDAC391, a myeloid‐targeted histone deacetylase inhibitor, shows enhanced pharmacology and monocytopaenia Furze, Rebecca C. Molnar, Judit Parr, Nigel J. Ahmad, Faiz Henry, Yvette Howe, David Singh, Rajendra Toal, Martin Bassil, Anna K. Bernard, Sharon G. Davis, Robert P. Gibson, Adele Maller, N. Claire Sharp, Catriona Tough, David F. Prinjha, Rab K. Lewis, Huw D. Br J Clin Pharmacol Original Articles AIMS: To improve the tolerability and therapeutic application of histone deacetylase inhibitors (HDACi), by application of an esterase‐sensitive motif (ESM), to target pharmacological activity directly to mononuclear myeloid cells expressing the processing enzyme carboxylesterase‐1 (CES1). METHODS: This first‐in‐human study comprised single and multiple ascending dose cohorts to determine safety and tolerability. Pharmacodynamic parameters included acetylation, cytokine inhibition and intracellular concentrations of processed acid metabolite in isolated monocytes. Mechanistic work was conducted in vitro and in a CES1/Es1e ( lo ) mouse strain. RESULTS: ESM‐HDAC391 showed transient systemic exposure (plasma half‐life of 21–30 min) but selective retention of processed acid for at least 12 hours, resulting in robust targeted mechanistic engagement (increased acetylation in monocytes plus inhibition of ex vivo stimulated cytokine production). ESM‐HDAC391 was well tolerated and clinical toxicities common to non‐targeted HDACi were not observed. ESM‐HDAC391 treatment was accompanied by the novel finding of a dose‐dependent monocyte depletion that was transient and reversible and which plateaued at 0.06 × 10(9) monocytes/L after repeat dosing with 20 or 40 mg. Characterisation of monocyte depletion in transgenic mice (CES1/Es1e ( lo )) suggested that colony stimulating factor 1 receptor loss on circulating cells contributed to ESM‐HDAC‐mediated depletion. Further mechanistic investigations using human monocytes in vitro demonstrated HDACi‐mediated change in myeloid fate through modulation of colony stimulating factor 1 receptor and downstream effects on cell differentiation. CONCLUSION: These findings demonstrate selective targeting of monocytes in humans using the ESM approach and identify monocytopaenia as a novel outcome of ESM‐HDACi treatment, with implications for potential benefit of these molecules in myeloid‐driven diseases. John Wiley and Sons Inc. 2022-07-11 2022-12 /pmc/articles/PMC9796293/ /pubmed/35655123 http://dx.doi.org/10.1111/bcp.15428 Text en © 2022 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Original Articles
Furze, Rebecca C.
Molnar, Judit
Parr, Nigel J.
Ahmad, Faiz
Henry, Yvette
Howe, David
Singh, Rajendra
Toal, Martin
Bassil, Anna K.
Bernard, Sharon G.
Davis, Robert P.
Gibson, Adele
Maller, N. Claire
Sharp, Catriona
Tough, David F.
Prinjha, Rab K.
Lewis, Huw D.
Phase 1 and preclinical profiling of ESM‐HDAC391, a myeloid‐targeted histone deacetylase inhibitor, shows enhanced pharmacology and monocytopaenia
title Phase 1 and preclinical profiling of ESM‐HDAC391, a myeloid‐targeted histone deacetylase inhibitor, shows enhanced pharmacology and monocytopaenia
title_full Phase 1 and preclinical profiling of ESM‐HDAC391, a myeloid‐targeted histone deacetylase inhibitor, shows enhanced pharmacology and monocytopaenia
title_fullStr Phase 1 and preclinical profiling of ESM‐HDAC391, a myeloid‐targeted histone deacetylase inhibitor, shows enhanced pharmacology and monocytopaenia
title_full_unstemmed Phase 1 and preclinical profiling of ESM‐HDAC391, a myeloid‐targeted histone deacetylase inhibitor, shows enhanced pharmacology and monocytopaenia
title_short Phase 1 and preclinical profiling of ESM‐HDAC391, a myeloid‐targeted histone deacetylase inhibitor, shows enhanced pharmacology and monocytopaenia
title_sort phase 1 and preclinical profiling of esm‐hdac391, a myeloid‐targeted histone deacetylase inhibitor, shows enhanced pharmacology and monocytopaenia
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9796293/
https://www.ncbi.nlm.nih.gov/pubmed/35655123
http://dx.doi.org/10.1111/bcp.15428
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