Phenotypic screening identifies a trisubstituted imidazo[1,2-a]pyridine series that induces differentiation in multiple AML cell lines.

Autor:	Josa-Culleré L; Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford, OX1 3TA, UK., Galan SRG; Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford, OX1 3TA, UK., Cogswell TJ; Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford, OX1 3TA, UK., Jackson TR; MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 9DS, UK., Jay-Smith M; Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford, OX1 3TA, UK., Mola L; Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford, OX1 3TA, UK., Greaves CR; Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford, OX1 3TA, UK., Carter TS; Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford, OX1 3TA, UK., Madden KS; Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford, OX1 3TA, UK., Trott S; Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford, OX1 3TA, UK., Zhang D; MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 9DS, UK., Bataille CJR; Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford, OX1 3TA, UK; Department of Pharmacology, University of Oxford, Mansfield Road, Oxford, OX1 3QT, UK., Davies SG; Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford, OX1 3TA, UK., Vyas P; MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 9DS, UK., Milne TA; MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 9DS, UK. Electronic address: thomas.milne@imm.ox.ac.uk., Naylor A; Alan Naylor Consultancy Ltd., Harston, Cambridge, CB22 7QJ, UK., Wynne GM; Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford, OX1 3TA, UK., Russell AJ; Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford, OX1 3TA, UK; Department of Pharmacology, University of Oxford, Mansfield Road, Oxford, OX1 3QT, UK. Electronic address: angela.russell@chem.ox.ac.uk.
Jazyk:	angličtina
Zdroj:	European journal of medicinal chemistry [Eur J Med Chem] 2023 Oct 05; Vol. 258, pp. 115509. Date of Electronic Publication: 2023 May 26.
DOI:	10.1016/j.ejmech.2023.115509
Abstrakt:	Acute myeloid leukaemia (AML) is an aggressive type of leukaemia with low rates of long-term survival. While the current standard of care is based on cytotoxic chemotherapy, a promising emerging approach is differentiation therapy. However, most current differentiating agents target specific mutations and are effective only in certain patient subtypes. To identify agents which may be effective in wider population cohorts, we performed a phenotypic screen with the myeloid marker CD11b and identified a compound series that was able to differentiate AML cell lines in vitro regardless of their mutation status. Structure-activity relationship studies revealed that replacing the formamide and catechol methyl ether groups with sulfonamide and indazole respectively improved the in vitro metabolic profile of the series while maintaining the differentiation profile in multiple cell lines. This optimisation exercise enabled progression of a lead compound to in vivo efficacy testing. Our work supports the promise of phenotypic screening to identify novel small molecules that induce differentiation in a wide range of AML subtypes. Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: A.J.R., T.A.M., S.G.D. and P.V. are founders and minor shareholders of OxStem Oncology, a subsidiary company of OxStem Ltd. A.J.R. is a paid consultant for OxStem Ltd. G.M.W. is a paid consultant for and minor shareholder of OxStem Ltd. T.A.M. is currently a paid consultant for and minor shareholder of Dark Blue Therapeutics Ltd. (Copyright © 2023. Published by Elsevier Masson SAS.)
Databáze:	MEDLINE
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