Tandutinib

Tandutinib (MLN518) is a potent, ATP-competitive and reversible inhibitor of Type III receptor tyrosine kinases (RTKs). In vitro, Tandutinib (MLN518) inhibits FLT3, c-KIT and PDGFRß with a median IC50 of approximately 30 nM. Tandutinib inhibited FLT3 phosphorylation, downstream signaling and malignant growth in vitro and in animal models. In cellular assays, Tandutinib inhibited the autophosphorylation of these receptors with an IC50 of approximately 200 nM. Tandutinib (MLN518) is quite selective; of the other receptor tyrosine kinases tested, only CSF-1R was inhibited to any appreciable degree. Based on Tandutinib's activity against the FLT3 receptor, Tandutinib was tested against a panel of clinically isolated FLT3 ITD gain of function mutants expressed in BaF3 cells. Both the W51 mutant and the WT FLT3 receptor showed a significant inhibition of receptor autophosphorylation with Tandutinib treatment. In studies of 5 different FLT3/ITD expressing cells, Tandutinib inhibited cell growth with an IC50 of 10-30 nM in all cases.