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.
David K Heidary  1 ,  George Huang ,  Diane Boucher ,  Jianguo Ma ,  Cornelia Forster ,  Ron Grey ,  Jinwang Xu ,  Michael Arnost ,  Deborah Choquette ,  Guanjing Chen ,  Jie-Hua Zhou ,  Yung-Mae Yao ,  Edward D Ball ,  Mark Namchuk ,  Robert J Davies ,  Greg Henkel
Affiliations
  • 1. University of Kentucky, Department of Chemistry, Lexington Kentucky 40506, United States.
PMID: 22221201 DOI: 10.1021/jm201198w
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.