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

  • J Med Chem. 2021 Nov 11;64(21):15608-15628. doi: 10.1021/acs.jmedchem.1c00574.
Laia Josa-Culleré  1 ,  Katrina S Madden  1 ,  Thomas J Cogswell  2 ,  Thomas R Jackson  3 ,  Tom S Carter  1 ,  Douzi Zhang  3 ,  Graham Trevitt  4 ,  Stephen G Davies  1 ,  Paresh Vyas  3 ,  Graham M Wynne  1 ,  Thomas A Milne  3 ,  Angela J Russell  1  2
Affiliations
  • 1. Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, U.K.
  • 2. Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, U.K.
  • 3. MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, NIHR Oxford Biomedical Research Centre Haematology Theme, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DS, U.K.
  • 4. XenoGesis Ltd., BioCity Nottingham, Pennyfoot Street, Nottingham NG1 1GF, Nottinghamshire, U.K.
PMID: 34672555 DOI: 10.1021/acs.jmedchem.1c00574
Abstract

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.

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