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

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

Author information

1
University of Kentucky, Department of Chemistry, Lexington Kentucky 40506, United States.

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.

PMID:
22221201
DOI:
10.1021/jm201198w
[Indexed for MEDLINE]

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