Efficacy of a Mer and Flt3 tyrosine kinase small molecule inhibitor, UNC1666, in acute myeloid leukemia
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Alisa B. Lee-Sherick1, Weihe Zhang2, Kelly K. Menachof1, Amanda A. Hill1, Sean Rinella1, Gregory Kirkpatrick1, Lauren S. Page1, Michael A. Stashko2, Craig T. Jordan3, Qi Wei4, Jing Liu2, Dehui Zhang2, Deborah DeRyckere1, Xiaodong Wang2, Stephen Frye2, H. Shelton Earp5, Douglas K. Graham1
1University of Colorado, Department of Pediatrics, Aurora, CO, USA
2University of North Carolina, Eshelman School of Pharmacy, Chapel Hill, NC, USA
3University of Colorado, Department of Medicine, Aurora, CO, USA
4Children's Hospital Colorado, Department of Pathology, Aurora, CO, USA
5University of North Carolina, Department of Medicine, Chapel Hill, NC, USA
Douglas K. Graham, e-mail: firstname.lastname@example.org
Keywords: Tyrosine kinase inhibitor, acute myeloid leukemia, TAM receptors
Received: October 24, 2014 Accepted: January 15, 2015 Published: February 10, 2015
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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