VX-322: A Novel Dual Receptor Tyrosine Kinase Inhibitor for the Treatment of Acute Myelogenous Leukemia
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- 作者：David K. Heidary ; 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
- 刊名：Journal of Medicinal Chemistry
- 出版年：2012
- 出版时间：January 26, 2012
- 年：2012
- 卷：55
- 期：2
- 页码：725-734
- 全文大小：423K
- 年卷期：v.55,no.2(January 26, 2012)
- ISSN：1520-4804
文摘
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 Ki values of <1 nM and a cellular IC50 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.