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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. [Display omitted] • A phenotypic assay based on the expression of CD11b identifies small molecules that differentiate diverse AML cells. • The phenotypic screen identifies a hit series based on an imidazo[1,2- a ]pyridine core. • The initial hit is optimised to improve solubility and metabolic stability. • The lead compound OXS007464 differentiates AML cells in vitro in a range of cell lines with a range of mutation status. • The lead compound OXS007464 has a favourable pharmacokinetic profile. [ABSTRACT FROM AUTHOR]