Efficacy of a Mer and Flt3 tyrosine kinase small molecule inhibitor, UNC1666, in acute myeloid leukemia

Oncotarget
Alisa B Lee-SherickDouglas K Graham

Abstract

Mer and Flt3 receptor tyrosine kinases have been implicated as therapeutic targets in acute myeloid leukemia (AML). In this manuscript we describe UNC1666, a novel ATP-competitive small molecule tyrosine kinase inhibitor, which potently diminishes Mer and Flt3 phosphorylation in AML. Treatment with UNC1666 mediated biochemical and functional effects in AML cell lines expressing Mer or Flt3 internal tandem duplication (ITD), including decreased phosphorylation of Mer, Flt3 and downstream effectors Stat, Akt and Erk, induction of apoptosis in up to 98% of cells, and reduction of colony formation by greater than 90%, compared to treatment with vehicle. These effects were dose-dependent, with inhibition of downstream signaling and functional effects correlating with the degree of Mer or Flt3 kinase inhibition. Treatment of primary AML patient samples expressing Mer and/or Flt3-ITD with UNC1666 also inhibited Mer and Flt3 intracellular signaling, induced apoptosis, and inhibited colony formation. In summary, UNC1666 is a novel potent small molecule tyrosine kinase inhibitor that decreases oncogenic signaling and myeloblast survival, thereby validating dual Mer/Flt3 inhibition as an attractive treatment strategy for AML.

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Citations

Nov 6, 2018·JCI Insight·Alisa B Lee-SherickDouglas K Graham
Nov 12, 2016·Cancers·Madeline G HueyDouglas K Graham
Mar 9, 2017·Scientific Reports·Stanley G KimaniRaymond B Birge
Dec 7, 2018·Cancers·Sherri K SmartDouglas K Graham
Sep 21, 2016·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Deborah DeRyckereDouglas K Graham
Jul 15, 2015·Molecular Cancer Therapeutics·Christopher T CummingsDouglas K Graham
Dec 19, 2020·Signal Transduction and Targeted Therapy·Jenna L CarterYubin Ge
Oct 30, 2020·International Journal of Molecular Sciences·Tae Hyun ParkByung Il Lee
Jul 30, 2016·Biochemical and Biophysical Research Communications·Chen ChenCheng Cheng Zhang
Mar 12, 2021·Advanced Functional Materials·Xuefei ZhouLeaf Huang
Apr 4, 2021·Cancers·Pia AehnlichPer Thor Straten

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Methods Mentioned

BETA
xenograft
flow cytometry
enzymatic assay
electrophoresis
immunoprecipitation

Software Mentioned

Modfit Cell Cycle Analysis
GraphPad Prism
CXP
ModFit
LabChip EZ Reader

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