1. VX-322: A Novel Dual Receptor Tyrosine Kinase Inhibitor for the Treatment of Acute Myelogenous Leukemia
- Author
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Diane M. Boucher, George Huang, Edward D. Ball, Guanjing Chen, David K. Heidary, Mark N. Namchuk, Jianguo Ma, Yung-Mae Yao, Jinwang Xu, Ron Grey, Forster Cornelia J, Greg Henkel, Jie-Hua Zhou, Michael J. Arnost, Robert J. Davies, and Deborah Choquette
- Subjects
Male ,Serum ,Cell Survival ,Morpholines ,Antineoplastic Agents ,Apoptosis ,Pharmacology ,Receptor tyrosine kinase ,Mice ,Myelogenous ,fluids and secretions ,hemic and lymphatic diseases ,Precursor cell ,Drug Discovery ,Tumor Cells, Cultured ,medicine ,Animals ,Humans ,CD135 ,Receptor ,IC50 ,chemistry.chemical_classification ,Mice, Inbred BALB C ,biology ,hemic and immune systems ,Triazoles ,medicine.disease ,Leukemia, Myeloid, Acute ,Proto-Oncogene Proteins c-kit ,Leukemia ,Enzyme ,fms-Like Tyrosine Kinase 3 ,chemistry ,embryonic structures ,biology.protein ,Molecular Medicine ,Neoplasm Transplantation - 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 of1 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.
- Published
- 2012