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Chemical Compound Review:

Tandutinib 4-[6-methoxy-7-[3-(1- piperidyl)propoxy]qui...

Synonyms: MLN-518, Kinome_3320, S1043_Selleck, MLN518, CHEMBL124660, ...

Deangelo, D.J. et al., Kelly, L.M. et al., Griswold, I.J. et al., Pandey, A. et al.

Pandey, Volkots, Seroogy, Rose, Yu, Lambing, Hutchaleelaha, Hollenbach, Abe, Giese, Scarborough, Deangelo, Stone, Heaney, Nimer, Paquette, Klisovic, Caligiuri, Cooper, Lecerf, Karol, Sheng, Holford, Curtin, Druker, Heinrich,

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Disease relevance of MLN 518

Because of the correlation between FLT3 internal tandem duplication (ITD) mutations and poor prognosis in acute myelogenous leukemia (AML), we conducted a phase 1 trial of tandutinib in 40 patients with either AML or high-risk myelodysplastic syndrome (MDS) [1].
Tandutinib was given orally in doses ranging from 50 mg to 700 mg twice daily The principal dose-limiting toxicity (DLT) of tandutinib was reversible generalized muscular weakness, fatigue, or both, occurring at doses of 525 mg and 700 mg twice daily [1].
CT53518, a novel selective FLT3 antagonist for the treatment of acute myelogenous leukemia (AML) [2].

High impact information on MLN 518

Western blotting showed that tandutinib inhibited phosphorylation of FLT3 in circulating leukemic blasts [1].
MLN518 (formerly CT53518) is a small molecule inhibitor of the FLT3, KIT, and platelet-derived growth-factor receptor (PDGFR) tyrosine kinases with significant activity in murine models of FLT3 ITD-positive leukemia [3].
An optimized analogue in this series, 75 (CT53518), inhibits Flt-3, betaPDGFR, and c-Kit receptor phosphorylation with IC(50) values of 50-200 nM, whereas 15-20-fold less potent activity against CSF-1R was observed [4].
In Ba/F3 cells expressing different FLT3-ITD mutants, CT53518 inhibited IL-3-independent cell growth and FLT3-ITD autophosphorylation with an IC(50) of 10-100 nM [2].
In human FLT3-ITD-positive AML cell lines, CT53518 induced apoptosis and inhibited FLT3-ITD phosphorylation, cellular proliferation, and signaling through the MAP kinase and PI3 kinase pathways [2].

Biological context of MLN 518

Phase 1 clinical results with tandutinib (MLN518), a novel FLT3 antagonist, in patients with acute myelogenous leukemia or high-risk myelodysplastic syndrome: safety, pharmacokinetics, and pharmacodynamics [1].

Anatomical context of MLN 518

Therapeutic efficacy of CT53518 was demonstrated both in a nude mouse model and in a murine bone marrow transplant model of FLT3-ITD-induced disease [2].

References

Phase 1 clinical results with tandutinib (MLN518), a novel FLT3 antagonist, in patients with acute myelogenous leukemia or high-risk myelodysplastic syndrome: safety, pharmacokinetics, and pharmacodynamics. Deangelo, D.J., Stone, R.M., Heaney, M.L., Nimer, S.D., Paquette, R.L., Klisovic, R.B., Caligiuri, M.A., Cooper, M.R., Lecerf, J.M., Karol, M.D., Sheng, S., Holford, N., Curtin, P.T., Druker, B.J., Heinrich, M.C. Blood (2006) [Pubmed]
CT53518, a novel selective FLT3 antagonist for the treatment of acute myelogenous leukemia (AML). Kelly, L.M., Yu, J.C., Boulton, C.L., Apatira, M., Li, J., Sullivan, C.M., Williams, I., Amaral, S.M., Curley, D.P., Duclos, N., Neuberg, D., Scarborough, R.M., Pandey, A., Hollenbach, S., Abe, K., Lokker, N.A., Gilliland, D.G., Giese, N.A. Cancer Cell (2002) [Pubmed]
Effects of MLN518, a dual FLT3 and KIT inhibitor, on normal and malignant hematopoiesis. Griswold, I.J., Shen, L.J., La Rosée, P., Demehri, S., Heinrich, M.C., Braziel, R.M., McGreevey, L., Haley, A.D., Giese, N., Druker, B.J., Deininger, M.W. Blood (2004) [Pubmed]
Identification of orally active, potent, and selective 4-piperazinylquinazolines as antagonists of the platelet-derived growth factor receptor tyrosine kinase family. Pandey, A., Volkots, D.L., Seroogy, J.M., Rose, J.W., Yu, J.C., Lambing, J.L., Hutchaleelaha, A., Hollenbach, S.J., Abe, K., Giese, N.A., Scarborough, R.M. J. Med. Chem. (2002) [Pubmed]

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