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

• Published in: Molecules (Basel, Switzerland) Vol. 26; no. 21; p. 6648
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 02.11.2021; MDPI
• Subjects: Acute myeloid leukemia; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; benzooxazepinones; CD11b; Cell differentiation; Cell Differentiation - drug effects; Cell growth; Cell Line, Tumor; Cells, Cultured; Chemistry Techniques, Synthetic; Chemotherapy; Cytotoxicity; Differentiation; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Leukemia; Leukemia, Myeloid, Acute; Medical prognosis; Metabolism; Molecular Structure; Morphology; Mutation; Myeloid leukemia; Patients; Pharmacokinetics; phenotypic screen; Population genetics; Structure-Activity Relationship; Survival; phenotypic screen; differentiation; acute myeloid leukemia; CD11b; benzooxazepinones
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules26216648

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[ ][1,4]oxazepin-2(3 )-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.