Design, Synthesis, and Evaluation of a Novel Dual Fms-Like Tyrosine Kinase 3/Stem Cell Factor Receptor (FLT3/c-KIT) Inhibitor for the Treatment of Acute Myelogenous Leukemia

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• 作者：Robert J. Davies ; Albert C. Pierce ; Cornelia Forster ; Ron Grey ; Jinwang Xu ; Michael Arnost ; Deborah Choquette ; Vincent Galullo ; Shi-Kai Tian ; Greg Henkel ; Guanjing Chen ; David K. Heidary ; Joanne Ma ; Cameron Stuver-Moody ; Mark Namchuk
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：October 27, 2011
• 年：2011
• 卷：54
• 期：20
• 页码：7184-7192
• 全文大小：954K
• 年卷期：v.54,no.20(October 27, 2011)
• ISSN：1520-4804

文摘

A high-throughput screen of our compound archive revealed a novel class of dual FMS-like tyrosine kinase 3 (FLT3)/c-KIT inhibitors. With the help of molecular modeling, this class was rapidly optimized for both potency against FLT3 and FLT3/c-KIT and excellent potency in cell-based assays, leading to dose-dependent cell death in acute myelogenous leukemia (AML) patient blast samples. Ultimately, the AML patient blast data defined the preferred target profile as we designed and evaluated a set of FLT3 selective and FLT3/c-KIT dual molecules. Further optimization for pharmacokinetic properties resulted in the selection of the dual FLT3/c-KIT inhibitor, N³-(4-(trans-4-morpholinocyclohexyl)phenyl)-1-(pyridin-2-yl)-1H-1,2,4-triazole-3,5-diamine, VX-322 (compound 37), to move forward to preclinical evaluation.