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.
|Cell lines||AML cells expressing FLT3-ITD|
|Preparation method||AML cell lines HL60 (AML-M3) and AML193 (AML-M5), KG-1, KG-1a, THP-1, and ALL cell line RS4;11 were purchased from ATCC (Bethesda, MD). Cells (initial count of 0.3* 105–1.0 *105) were washed three times in RPMI 1640 medium and plated in 1 ml of complete growth media (without IL-3 for the Ba/F3 cells) in the presence of increasing concentrations of CT53518 (0.004–30 μM). Cells were grown for 3–7 days in tissue culture, and viable cells, determined by Trypan blue dye exclusion, were counted.|
|Incubation time||3 days|
|Animal models||Ba/F3 nude mouse model of FLT3-ITD-mediated leukemia|
|Formulation||0.5% methyl cellulose|
|Dosages||60 mg/kg BID day 7-57|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
Preclinical testing of tandutinib in a transgenic medulloblastoma mouse model.
Ohshima-Hosoyama et al. J Pediatr Hematol Oncol. 2012 Mar;34(2):116-21. PMID: 22146535.
Multidimensional profiling of CSF1R screening hits and inhibitors: assessing cellular activity, target residence time, and selectivity in a higher throughput way.
Uitdehaag et al. J Biomol Screen. 2011 Oct;16(9):1007-17. PMID: 21873591.
Accelerated disease progression in prostate cancer and bone metastases with platelet-derived growth factor receptor inhibition: observations with tandutinib.
Mathew et al. Cancer Chemother Pharmacol. 2011 Oct;68(4):889-96. PMID: 21290244.
Neuromuscular junction toxicity with tandutinib induces a myasthenic-like syndrome.
Lehky et al. Neurology. 2011 Jan 18;76(3):236-41. PMID: 21242491.
CT53518, a novel selective FLT3 antagonist for the treatment of acute myelogenous leukemia (AML).
Kelly LM, et al. Cancer Cell. 2002 Jun;1(5):421-32. PMID: 12124172.
|Related FLT3 Products|
Gilteritinib is a potent FLT3/AXL inhibitor with IC50 of 0.29 nM/0.73 nM, respectively.
AMG 925 is a potent and orally bioavailable dual FLT3/CDK4 inhibitor with IC50 of 1 nM and 3 nM, respectively.
G-749 is a novel and potent FLT3 inhibitor with IC50 of 0.4 nM, 0.6 nM and 1 nM for FLT3 (WT), FLT3 (D835Y), and Mer, respectively, showing lower potency against other tyrosine kinases.
UNC-2025 is a potent and orally bioavailable dual MER/FLT3 inhibitor with IC50 of 0.74 nM and 0.8 nM, respectively, about 20-fold selectivity over Axl and Tyro3.
CGP52421 is a FLT3 inhibitor, which is also an metabolite of midostaurin (PKC412).
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