Abstract
Acute myeloid leukemia (AML) is the most aggressive type of blood cancer, and there is a continued need for new treatments that are well tolerated and improve long-term survival rates in patients. Induction of differentiation has emerged as a promising alternative to conventional cytotoxic chemotherapy, but known agents lack efficacy in genetically distinct patient populations. Previously, we established a phenotypic screen to identify small molecules that could stimulate differentiation in a range of AML cell lines. Utilising this strategy, a 1,5-dihydrobenzo[e][1,4]oxazepin-2(3H)-one hit compound was identified. Herein, we report the hit validation in vitro, structure-activity relationship (SAR) studies and the pharmacokinetic profiles for selected compounds.
Highlights
Acute myeloid leukemia (AML) is a type of blood cancer characterised by a block in differentiation of cells of the myeloid lineage
Within our effort to identify novel differentiating agents for AML, we developed a phenotypic screen with different AML cell lines representing different disease subtypes and measured the myeloid marker CD11b as a primary readout
The expression of CD11b was selected as the primary readout, as CD11b is upregulated upon myeloid differentiation [19,20]
Summary
Acute myeloid leukemia (AML) is a type of blood cancer characterised by a block in differentiation of cells of the myeloid lineage. Their abnormal growth and differentiation lead to an accumulation of immature myeloid precursors in the bone marrow and peripheral blood, which disrupts the formation of terminally differentiated blood cells. The current standard of care (SOC) consists of induction therapy using cytarabine and an anthracycline, followed by consolidation chemotherapy or allogeneic stem cell transplant [3]. The majority of AML cases are elderly (>65 years of age) and do not tolerate this intensive chemotherapy well. There is a clear need for new treatments that are better tolerated and that provide high long-term survival
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