VX-322: a novel dual receptor tyrosine kinase inhibitor for the treatment of acute myelogenous leukemia.

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Heidary DK, Huang G, Boucher D, Ma J, Forster C, Grey R, Xu J, Arnost M, Choquette D, Chen G, Zhou JH, Yao YM, Ball ED, Namchuk M, Davies RJ, Henkel G

VX-322: a novel dual receptor tyrosine kinase inhibitor for the treatment of acute myelogenous leukemia.

J Med Chem. 2012 Jan 26;55(2):725-34. doi: 10.1021/jm201198w. Epub 2012 Jan 5.

PubMed ID
22221201 [ View in PubMed
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Abstract

In acute myelogenous leukemia (AML), the FLT3 receptor tyrosine kinase (RTK) is highly expressed with 30% of patients expressing a mutated, constitutively active form of this protein. To inhibit this receptor, VX-322 was developed and found to be very potent against both the FLT3 and c-KIT RTKs with enzyme K(i) values of <1 nM and a cellular IC(50) between 1 and 5 nM. It was efficacious in a FLT3-ITD dependent myeloproliferative mouse model, doubling survival compared to other FLT3 inhibitors, with 25% of the mice cured. Upon treatment of primary AML patient blast cells, the dual inhibition of FLT3 and c-KIT was superior to inhibitors targeting a single RTK. Thus, this compound may represent an improved pharmacologic and selectivity profile that could be effective in the treatment of AML.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
SunitinibReceptor-type tyrosine-protein kinase FLT3IC 50 (nM)8N/AN/ADetails
SunitinibVascular endothelial growth factor receptor 2IC 50 (nM)8N/AN/ADetails
TandutinibReceptor-type tyrosine-protein kinase FLT3IC 50 (nM)200N/AN/ADetails