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

MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, NIHR Oxford Biomedical Research Centre Haematology Theme, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DS, UK

Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, UK

Authors to whom correspondence should be addressed.

Academic Editor: Giosuè Costa

Molecules 2021, 26(21), 6648; https://doi.org/10.3390/molecules26216648

Received: 21 September 2021 / Revised: 18 October 2021 / Accepted: 18 October 2021 / Published: 2 November 2021

(This article belongs to the Special Issue Phenotypic Screening)

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Abstract

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. View Full-Text

Keywords: acute myeloid leukemia; differentiation; phenotypic screen; CD11b; benzooxazepinones

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MDPI and ACS Style

Josa-Culleré, L.; Cogswell, T.J.; Georgiou, I.; Jay-Smith, M.; Jackson, T.R.; Bataille, C.J.R.; Davies, S.G.; Vyas, P.; Milne, T.A.; Wynne, G.M.; Russell, A.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. Molecules 2021, 26, 6648. https://doi.org/10.3390/molecules26216648

AMA Style

Josa-Culleré L, Cogswell TJ, Georgiou I, Jay-Smith M, Jackson TR, Bataille CJR, Davies SG, Vyas P, Milne TA, Wynne GM, Russell AJ. 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. Molecules. 2021; 26(21):6648. https://doi.org/10.3390/molecules26216648

Chicago/Turabian Style

Josa-Culleré, Laia, Thomas J. Cogswell, Irene Georgiou, Morgan Jay-Smith, Thomas R. Jackson, Carole J. R. Bataille, Stephen G. Davies, Paresh Vyas, Thomas A. Milne, Graham M. Wynne, and Angela J. Russell. 2021. "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" Molecules 26, no. 21: 6648. https://doi.org/10.3390/molecules26216648

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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

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