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Ref Type

Journal Article

PMID

(25762638)

Authors

Lee-Sherick AB, Zhang W, Menachof KK, Hill AA, Rinella S, Kirkpatrick G, Page LS, Stashko MA, Jordan CT, Wei Q, Liu J, Zhang D, DeRyckere D, Wang X, Frye S, Earp HS, Graham DK

Title

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

Journal	Vol	Issue	Date	Pages	Journal Short Title
Oncotarget	6	9	2015 Mar 30	6722-36	Oncotarget

URL

Abstract Text

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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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
UNC1666	UNC1666	1	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
UNC1666			FLT3 Inhibitor 69 MERTK Inhibitor 13	UNC1666 is an ATP-competitive inhibitor of Mertk and FLT3 that may inhibit tumor cell growth (PMID: 25762638).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
FLT3 exon 14 ins	acute myeloid leukemia	sensitive	UNC1666	Preclinical - Cell culture	Actionable	In a preclinical study, UNC1666 inhibited FLT3 phosphorylation and downstream signaling, induced apoptosis of acute myeloid leukemia cells harboring FLT3 exon 14 insertions (ITD) in culture (PMID: 25762638).	25762638