• Tandutinib (also known as MLN518 or CT53518) is an orally active inhibitor of Fms-like tyrosine kinase 3 (FLT3) kinase, PDGFRβ and c-Kit. It inhibits FLT3 phosphorylation, downstream signaling and tumor growth in vitro and in animal models. Cheng, Y. and Paz, K. "Tandutinib, an oral, small-molecule inhibitor of FLT3 for the treatment of AML and other cancer indications." IDrugs 11: 46-56 (2008).
• The sensitivity of cell lines to tandutinib is increased by FLT3 siRNA-induced down-regulation of FLT3. Walters, D.K., et al. "RNAi-induced down-regulation of FLT3 expression in AML cell lines increases sensitivity to MLN518." Blood 105: 2952-2954 (2005).
• In human FLT3-ITD-positive acute myelogenous leukemia (AML) cell lines, tandutinib induced apoptosis and inhibited FLT3-ITD phosphorylation, cellular proliferation, and signaling through the MAP kinase and PI3 kinase pathways. In Ba/F3 cells expressing different FLT3-ITD mutants, tandutinib also demonstrated inhibition of IL-3-independent cell growth and FLT3-ITD autophosphorylation, with an IC50 of 10-100 nM. Tandutinib was a potent inhibitor of FLT3-ITD-induced disease in a murine model. Kelly, L.M., et al. "CT53518, a novel selective FLT3 antagonist for the treatment of acute myelogenous leukemia (AML)." Cancer Cell 1: 421-432 (2002).
• Tandutinib inhibits the growth of blast colonies from FLT3 ITD-positive patients with acute myelocytic leukemia (AML) more effectively than for blast colonies from ITD-negative AML patients, at concentrations that do not significantly block colony formation of normal human progenitor cells. Tandutinib has moderate toxicity toward normal hematopoiesis at concentrations that are used in treating FLT3 ITD-positive leukemia in mice. Griswold, I.J., et al. "Effects of MLN518, a dual FLT3 and KIT inhibitor, on normal and malignant hematopoiesis." Blood 104: 2912-2918 (2004).
• Tandutinib inhibited FLT3 autophosphorylation and phosphorylation of STAT5 and ERK in FLT3-ITD-transformed Ba/F3 cells (IC50 = 500 nM). However, there was a broad spectrum of sensitivity among the 8 activation loop mutants (IC50 = 500 nM - 10 µM) for the inhibition of phosphorylation of FLT3, STAT5, and ERK. The relative cellular sensitivity of the mutants to tandutinib for proliferation of FLT3-transformed Ba/F3 cells correlated with IC50s in the biochemical assays, indicating that certain activation loop mutations in FLT3 confer resistance to tandutinib. Clark, J.J., et al. "Variable sensitivity of FLT3 activation loop mutations to the small molecule tyrosine kinase inhibitor MLN518." Blood 104: 2867-2872 (2004).
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