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

Laia Josa-Culleré,Tom S Carter,Thomas J Cogswell,Thomas R Jackson,Graham M Wynne,Paresh Vyas,Douzi Zhang,Stephen G Davies,Thomas A Milne,Angela J Russell,Katrina S Madden,Graham Trevitt

doi:10.1021/acs.jmedchem.1c00574

Laia Josa-Culleré, Tom S Carter + Show 10 more

Open Access

https://doi.org/10.1021/acs.jmedchem.1c00574

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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.

Highlights

Acute myeloid leukemia (AML) is the most aggressive type of blood cancer and the second most common leukemia in adults.AML arises from genetic mutations, which cause an arrest of differentiation at the progenitor or precursor stage, blocking production of downstream blood lineages
To find new small molecules that can differentiate AML cells, the cell-surface marker CD11b was chosen as it is upregulated upon myeloid differentiation regardless of the lineage that the cells specialize into
Cells were stained with CD11b-PE and DAPI, and upregulation of CD11b in the live cells was detected via flow cytometry

Summary

Introduction

AML arises from genetic mutations, which cause an arrest of differentiation at the progenitor or precursor stage, blocking production of downstream blood lineages. This differentiation block produces cells that can still proliferate leading to the accumulation of immature myeloid cells blasts in the bone marrow and peripheral blood, which disrupts normal hematopoiesis.[1] AML can occur at all ages but predominantly affects elderly people, with 80% of patients being over 60 years of age.[2,3]. The standard of care for many years has been intensive chemotherapy with cytarabine in combination with anthracycline-derived antibiotics such as daunorubicin to induce apoptosis of AML blasts, which often cannot be tolerated by elderly patients

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