A Phenotypic Screen Identifies a Compound Series That Induces Differentiation of Acute Myeloid Leukemia Cells In Vitro and Shows Antitumor Effects In Vivo.

Josa-Culleré L., Madden KS., Cogswell TJ., Jackson TR., Carter TS., Zhang D., Trevitt G., Davies SG., Vyas P., Wynne GM., Milne TA., Russell AJ.

Induction of differentiation is a promising therapeutic strategy against acute myeloid leukemia. However, current differentiation therapies are effective only to specific patient populations. To identify novel differentiation agents with wider efficacy, we developed a phenotypic high-throughput screen with a range of genetically diverse cell lines. From the resulting hits, one chemical scaffold was optimized in terms of activity and physicochemical properties to yield OXS007417, a proof-of-concept tool compound, which was also able to decrease tumor volume in a murine in vivo xenograft model.

DOI

10.1021/acs.jmedchem.1c00574

Type

Journal article

Journal

J Med Chem

Publication Date

11/11/2021

Volume

64

Pages

15608 - 15628

Keywords

Animals, Antineoplastic Agents, Cell Differentiation, Cell Survival, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Female, Humans, Leukemia, Myeloid, Acute, Male, Mice, Mice, Inbred NOD, Mice, SCID, Molecular Structure, Neoplasms, Experimental, Phenotype, Structure-Activity Relationship, Tumor Cells, Cultured

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