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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.

Original publication

DOI

10.1016/j.ejmech.2023.115509

Type

Journal article

Journal

Eur J Med Chem

Publication Date

05/10/2023

Volume

258

Keywords

Acute myeloid leukaemia, Differentiation therapy, Imidazo[1,2-a]pyridines, Humans, Leukemia, Myeloid, Acute, Antineoplastic Agents, Cell Line, Cell Differentiation, Pyridines