title: Efficacy of a Mer and Flt3 tyrosine kinase small molecule inhibitor, UNC1666, in acute myeloid leukemia.
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.
authors.affiliation: University of Colorado, Department of Pediatrics, Aurora, CO, USA.
authors.forename: Alisa B
authors.initials: AB
authors.lastname: Lee-Sherick
authors.affiliation: University of North Carolina, Eshelman School of Pharmacy, Chapel Hill, NC, USA.
authors.forename: Weihe
authors.initials: W
authors.lastname: Zhang
authors.affiliation: University of Colorado, Department of Pediatrics, Aurora, CO, USA.
authors.forename: Kelly K
authors.initials: KK
authors.lastname: Menachof
authors.affiliation: University of Colorado, Department of Pediatrics, Aurora, CO, USA.
authors.forename: Amanda A
authors.initials: AA
authors.lastname: Hill
authors.affiliation: University of Colorado, Department of Pediatrics, Aurora, CO, USA.
authors.forename: Sean
authors.initials: S
authors.lastname: Rinella
authors.affiliation: University of Colorado, Department of Pediatrics, Aurora, CO, USA.
authors.forename: Gregory
authors.initials: G
authors.lastname: Kirkpatrick
authors.affiliation: University of Colorado, Department of Pediatrics, Aurora, CO, USA.
authors.forename: Lauren S
authors.initials: LS
authors.lastname: Page
authors.affiliation: University of North Carolina, Eshelman School of Pharmacy, Chapel Hill, NC, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Stashko
authors.affiliation: University of Colorado, Department of Medicine, Aurora, CO, USA.
authors.forename: Craig T
authors.initials: CT
authors.lastname: Jordan
authors.affiliation: Children's Hospital Colorado, Department of Pathology, Aurora, CO, USA.
authors.forename: Qi
authors.initials: Q
authors.lastname: Wei
authors.affiliation: University of North Carolina, Eshelman School of Pharmacy, Chapel Hill, NC, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Liu
authors.affiliation: University of North Carolina, Eshelman School of Pharmacy, Chapel Hill, NC, USA.
authors.forename: Dehui
authors.initials: D
authors.lastname: Zhang
authors.affiliation: University of Colorado, Department of Pediatrics, Aurora, CO, USA.
authors.forename: Deborah
authors.initials: D
authors.lastname: DeRyckere
authors.affiliation: University of North Carolina, Eshelman School of Pharmacy, Chapel Hill, NC, USA.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Wang
authors.affiliation: University of North Carolina, Eshelman School of Pharmacy, Chapel Hill, NC, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Frye
authors.affiliation: University of North Carolina, Department of Medicine, Chapel Hill, NC, USA.
authors.forename: H Shelton
authors.initials: HS
authors.lastname: Earp
authors.affiliation: University of Colorado, Department of Pediatrics, Aurora, CO, USA.
authors.forename: Douglas K
authors.initials: DK
authors.lastname: Graham
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D042381:Granulocyte Precursor Cells / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D058990:Molecular Targeted Therapy; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured; D000076202:c-Mer Tyrosine Kinase; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D011743:Pyrimidines; D011758:Pyrroles; C000604214:UNC1666; C497970:FLT3 protein, human; C097072:MERTK protein, human; D020794:Receptor Protein-Tyrosine Kinases; D000076202:c-Mer Tyrosine Kinase; D051941:fms-Like Tyrosine Kinase 3
keywords: TAM receptors; acute myeloid leukemia; tyrosine kinase inhibitor