Tandutinib (MLN518)

Tandutinib (MLN518, CT53518) is a novel, selective and small-molecule inhibitor of FLT3 with IC50 value of 0.22μM [1].

Tandutinib (MLN518) has been reported to inhibit FLT3, PDGFR and c-Kit in in vitro kinase assays with IC50 values of 0.22μM, 0.20μM and 0.17μM, respectively. In addition, Tandutinib (MLN518) has been revealed to inhibit wild-type FLT3 or W51 tyrosine phosphorylation with an IC50 value of 30–100 nM. Furthermore, Tandutinib (MLN518) has shown the cell antiproliferation of the FLT3-ITD-positive cells （Molm-13 and Molm-14 cells） with an IC50 value of 10 nM, whereas the FLT3-ITD-negative cells ( THP-1, KG-1, and RS4 cells) were resistant, requiring 1000-fold higher concentrations to inhibit cell growth [1]

References:
[1] Kelly LM1, Yu JC, Boulton CL, Apatira M, Li J, Sullivan CM, Williams I, Amaral SM, Curley DP, Duclos N, Neuberg D, Scarborough RM, Pandey A, Hollenbach S, Abe K, Lokker NA, Gilliland DG, Giese NA. CT53518, a novel selective FLT3 antagonist for the treatment of acute myelogenous leukemia (AML). Cancer Cell. 2002 Jun;1(5):421-32.

Tandutinib (MLN518) reverses multidrug resistance by inhibiting the efflux activity of the multidrug resistance protein 7 (ABCC10).[Pubmed:23525656]

Oncol Rep. 2013 Jun;29(6):2479-85.

It is well established that ATP-binding cassette (ABC) transporter-mediated multidrug resistance (MDR) is one of the major mechanisms that causes resistance to antineoplastic drugs in cancer cells. ABC transporters can significantly decrease the intracellular concentration of antineoplastic drugs by increasing their efflux, thereby lowering their cytotoxic activity. One of these transporters, the multidrug resistance protein 7 (MRP7/ABCC10), has already been shown to produce resistance to antineoplastic drugs by increasing the efflux of the drugs. In the present study, we investigated whether tandutinib, an FMS-like tyrosine kinase 3 (FLT3) inhibitor, has the potential to reverse MRP7-mediated MDR. Our results revealed that tandutinib significantly enhanced the sensitivity of MRP7-transfected HEK293 cells to the 2 established MRP7 substrates, paclitaxel and vincristine, whereas there was less or no effect on the control vector-transfected HEK293 cells. [(3)H]-paclitaxel accumulation and efflux studies demonstrated that tandutinib increased the intracellular accumulation of [(3)H]-paclitaxel and inhibited the efflux of [(3)H]-paclitaxel from HEK-MRP7 cells. In addition, western blot analysis showed that tandutinib did not significantly affect MRP7 expression. Thus, we conclude that the FLT3 inhibitor tandutinib can reverse MRP7-mediated MDR through inhibition of the drug efflux function and may have potential to be used clinically in combination therapy for cancer patients.

Tandutinib (MLN518/CT53518) targeted to stem-like cells by inhibiting the function of ATP-binding cassette subfamily G member 2.[Pubmed:23619284]

Eur J Pharm Sci. 2013 Jun 14;49(3):441-50.

Tandutinib is a novel inhibitor of tyrosine kinases FLT3, PDGFR and KIT. Our study was to explore the capability of tandutinib to reverse ABC transporter-mediated multidrug resistance. Tandutinib reversed ABCG2-mediated drug resistance in ABCG2-482-R2, ABCG2-482-G2, ABCG2-482-T7 and S1-M1-80 cells and increased the accumulation of doxorubicin, rhodamine 123 and [H(3)] mitoxantrone in ABCG2-overexpressing cells. Importantly, tandutinib selectively sensitized side population cells to mitoxantrone. Taken together, our results advocate the potency of tandutinib as an ABCG2 modulator and stem-like cells targeted agent to increase efficiency of anticancer drugs.

The FLT3 inhibitor tandutinib (formerly MLN518) has sequence-independent synergistic effects with cytarabine and daunorubicin.[Pubmed:19625780]

Cell Cycle. 2009 Aug 15;8(16):2621-30.

AML remains a difficult disease to treat. Despite response to induction chemotherapy, most patients ultimately relapse. Further, among elderly patients, aggressive therapy options are often limited due to other medical conditions and decreased tolerance of these patients to conventional chemotherapy. Internal tandem duplications (ITD) of the FLT3 juxtamembrane domain occur in 20-30% of AML patients and predict poor outcome. First clinical data with the FLT3 inhibitor tandutinib demonstrated antileukemic activity in approximately half of the patients--predominantly with FLT3 ITD positive AML. But the data also show that optimal use of tandutinib will require combination therapy with cytotoxic agents. Notably, single agent tandutinib has not been associated with myelosuppression, mucositis or cardiac toxicity--the dose limiting toxicities of AML chemotherapy. We determined the feasibility of combining tandutinib with the standard "3 + 7" induction regimen in AML and show that, in contrast to other structurally unrelated FLT3 inhibitors recently evaluated in clinical trials, the use of tandutinib displayed application sequence independent synergistic antileukemic effects in combination with cytarabine and daunorubicin. Strong synergistic antiproliferative and proapoptotic effects were thereby predominantly seen on FLT3 ITD positive blasts. Further we demonstrate, that addition of tandutinib may allow dose reduction of chemotherapy without loss of overall antileukemic activity--resulting in a potential decrease of side effects. This approach might be an interesting novel strategy especially in the treatment of elderly/comorbid patients. Our data provide a rationale for combining tandutinib with induction chemotherapy in intensified as well as in dose reduction protocols for FLT3 ITD positive AML.

A phase II study of tandutinib (MLN518), a selective inhibitor of type III tyrosine receptor kinases, in patients with metastatic renal cell carcinoma.[Pubmed:20711630]

Invest New Drugs. 2012 Feb;30(1):364-7.

Therapies which target VEGF and mTOR are now available for patients with metastatic renal cell carcinoma, but there is a continued need to develop agents for patients who become refractory to these initial agents. Tandutinib is a relatively selective inhibitor of type III tyrosine kinase receptor kinases with promising activity in some tumors. In this trial, 10 patients with metastatic renal cell carcinoma refractory to previous therapy with sunitinib or sorafenib (median age 61 years, 80% performance status 0, 60% intermediate MSKCC risk classification) received tandutinib 500 mg bid daily with RECIST-defined response as the primary endpoint and progression-free survival (PFS) and overall survival (OS) as secondary endpoints. No patient had more than 2 cycles of therapy and 50% of patients only received 1 cycle with 70% of patients discontinuing for progressive disease and 30% for toxicity. Tandutinib was not well tolerated with dose reduction in 60% of patients due to adverse events. The most common grade 3 toxicity was fatigue (30%). Tandutinib had no clinical activity and due to the excessive toxicity should not be developed further in patients with sunitinib or sorafenib-refractory metastatic renal cell carcinoma.

Tandutinib (MLN518) is a potent and selective inhibitor of the FLT3 with an IC50 of 0.22 μM, and also inhibits c-Kit and PDGFR with IC50s of 0.17 μM and 0.20 μM, respectively. Tandutinib can be used for acute myelogenous leukemia (AML). Tandutinib has the ability to cross the blood-brain barrier.

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