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]
- 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
Drug Target Property Measurement pH Temperature (°C) Sunitinib Receptor-type tyrosine-protein kinase FLT3 IC 50 (nM) 8 N/A N/A Details Sunitinib Vascular endothelial growth factor receptor 2 IC 50 (nM) 8 N/A N/A Details Tandutinib Receptor-type tyrosine-protein kinase FLT3 IC 50 (nM) 200 N/A N/A Details