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

Alisa B. Lee-Sherick, Weihe Zhang, Kelly K. Menachof, Amanda A. Hill, Sean Rinella, Gregory Kirkpatrick, Lauren S. Page, Michael A. Stashko, Craig T. Jordan, Qi Wei, Jing Liu, Dehui Zhang, Deborah DeRyckere, Xiaodong Wang, Stephen Frye, H. Shelton Earp, Douglas K. Graham

Research output: Contribution to journalArticlepeer-review

38 Scopus citations

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.

Original languageEnglish
Pages (from-to)6722-6736
Number of pages15
JournalOncotarget
Volume6
Issue number9
DOIs
StatePublished - 2015
Externally publishedYes

Keywords

  • Acute myeloid leukemia
  • TAM receptors
  • Tyrosine kinase inhibitor

Fingerprint

Dive into the research topics of 'Efficacy of a Mer and Flt3 tyrosine kinase small molecule inhibitor, UNC1666, in acute myeloid leukemia'. Together they form a unique fingerprint.

Cite this