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Identification and Preliminary Structure-Activity Relationship Studies of 1,5-Dihydrobenzo[e][1,4]oxazepin-2(3H)-ones That Induce Differentiation of Acute Myeloid Leukemia Cells In Vitro

Acute myeloid leukemia (AML) is the most aggressive type of blood cancer, and there is a continued need for new treatments that are well tolerated and improve long-term survival rates in patients. Induction of differentiation has emerged as a promising alternative to conventional cytotoxic chemother...

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Autores principales: Josa-Culleré, Laia, Cogswell, Thomas J., Georgiou, Irene, Jay-Smith, Morgan, Jackson, Thomas R., Bataille, Carole J. R., Davies, Stephen G., Vyas, Paresh, Milne, Thomas A., Wynne, Graham M., Russell, Angela J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8588310/
https://www.ncbi.nlm.nih.gov/pubmed/34771052
http://dx.doi.org/10.3390/molecules26216648
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author Josa-Culleré, Laia
Cogswell, Thomas J.
Georgiou, Irene
Jay-Smith, Morgan
Jackson, Thomas R.
Bataille, Carole J. R.
Davies, Stephen G.
Vyas, Paresh
Milne, Thomas A.
Wynne, Graham M.
Russell, Angela J.
author_facet Josa-Culleré, Laia
Cogswell, Thomas J.
Georgiou, Irene
Jay-Smith, Morgan
Jackson, Thomas R.
Bataille, Carole J. R.
Davies, Stephen G.
Vyas, Paresh
Milne, Thomas A.
Wynne, Graham M.
Russell, Angela J.
author_sort Josa-Culleré, Laia
collection PubMed
description Acute myeloid leukemia (AML) is the most aggressive type of blood cancer, and there is a continued need for new treatments that are well tolerated and improve long-term survival rates in patients. Induction of differentiation has emerged as a promising alternative to conventional cytotoxic chemotherapy, but known agents lack efficacy in genetically distinct patient populations. Previously, we established a phenotypic screen to identify small molecules that could stimulate differentiation in a range of AML cell lines. Utilising this strategy, a 1,5-dihydrobenzo[e][1,4]oxazepin-2(3H)-one hit compound was identified. Herein, we report the hit validation in vitro, structure-activity relationship (SAR) studies and the pharmacokinetic profiles for selected compounds.
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spelling pubmed-85883102021-11-13 Identification and Preliminary Structure-Activity Relationship Studies of 1,5-Dihydrobenzo[e][1,4]oxazepin-2(3H)-ones That Induce Differentiation of Acute Myeloid Leukemia Cells In Vitro Josa-Culleré, Laia Cogswell, Thomas J. Georgiou, Irene Jay-Smith, Morgan Jackson, Thomas R. Bataille, Carole J. R. Davies, Stephen G. Vyas, Paresh Milne, Thomas A. Wynne, Graham M. Russell, Angela J. Molecules Article Acute myeloid leukemia (AML) is the most aggressive type of blood cancer, and there is a continued need for new treatments that are well tolerated and improve long-term survival rates in patients. Induction of differentiation has emerged as a promising alternative to conventional cytotoxic chemotherapy, but known agents lack efficacy in genetically distinct patient populations. Previously, we established a phenotypic screen to identify small molecules that could stimulate differentiation in a range of AML cell lines. Utilising this strategy, a 1,5-dihydrobenzo[e][1,4]oxazepin-2(3H)-one hit compound was identified. Herein, we report the hit validation in vitro, structure-activity relationship (SAR) studies and the pharmacokinetic profiles for selected compounds. MDPI 2021-11-02 /pmc/articles/PMC8588310/ /pubmed/34771052 http://dx.doi.org/10.3390/molecules26216648 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/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 (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Josa-Culleré, Laia
Cogswell, Thomas J.
Georgiou, Irene
Jay-Smith, Morgan
Jackson, Thomas R.
Bataille, Carole J. R.
Davies, Stephen G.
Vyas, Paresh
Milne, Thomas A.
Wynne, Graham M.
Russell, Angela J.
Identification and Preliminary Structure-Activity Relationship Studies of 1,5-Dihydrobenzo[e][1,4]oxazepin-2(3H)-ones That Induce Differentiation of Acute Myeloid Leukemia Cells In Vitro
title Identification and Preliminary Structure-Activity Relationship Studies of 1,5-Dihydrobenzo[e][1,4]oxazepin-2(3H)-ones That Induce Differentiation of Acute Myeloid Leukemia Cells In Vitro
title_full Identification and Preliminary Structure-Activity Relationship Studies of 1,5-Dihydrobenzo[e][1,4]oxazepin-2(3H)-ones That Induce Differentiation of Acute Myeloid Leukemia Cells In Vitro
title_fullStr Identification and Preliminary Structure-Activity Relationship Studies of 1,5-Dihydrobenzo[e][1,4]oxazepin-2(3H)-ones That Induce Differentiation of Acute Myeloid Leukemia Cells In Vitro
title_full_unstemmed Identification and Preliminary Structure-Activity Relationship Studies of 1,5-Dihydrobenzo[e][1,4]oxazepin-2(3H)-ones That Induce Differentiation of Acute Myeloid Leukemia Cells In Vitro
title_short Identification and Preliminary Structure-Activity Relationship Studies of 1,5-Dihydrobenzo[e][1,4]oxazepin-2(3H)-ones That Induce Differentiation of Acute Myeloid Leukemia Cells In Vitro
title_sort identification and preliminary structure-activity relationship studies of 1,5-dihydrobenzo[e][1,4]oxazepin-2(3h)-ones that induce differentiation of acute myeloid leukemia cells in vitro
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8588310/
https://www.ncbi.nlm.nih.gov/pubmed/34771052
http://dx.doi.org/10.3390/molecules26216648
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