Document Report Card

ID: ALA1955771

Journal: J Med Chem

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

Authors: 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.

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.

CiteXplore: 22221201

DOI: 10.1021/jm201198w