TAK-243-DataSheet-MedChemExpress

TAK-243

carcinoma transplant (SCCT) and SCCRDEBMet cells are the most susceptible to continuous treatment with TAK-243.

SCCIC1Met cells are also selectively killed by an extended exposure to TAK-243. Death in SCCRDEBMet cells displays

the greatest sensitivity to a pulse of TAK-243. MLN7243 can reduce the cellular level of ubiquitin conjugates. TAK-243

decreases UBA1 and UBA6 thioesters and thioesters of the UBA6 specific E2 UBE2Z/USE1[1]. TAK-243 displays

preferential activity towards acute myeloid leukemia (AML) cells over normal hematopoietic cells. TAK-243 reduces

growth and viability of human AML cell lines (OCI-AML2, TEX, U937 and NB4) in a concentration- and time-

dependent manner with IC50 's ranging from 15-40 nM after treatment for 48 hours[2].

In Vivo TAK-243 significantly delays tumor growth in mice (T/C=0.02) with no toxicity as evidenced by no changes in mouse body weight, serum chemistry, or organ histology. TAK-243 reduces primary AML tumor burden in both tested

samples without toxicity[2].

PROTOCOL

Cell Assay [1]Normal keratinocytes (normal human keratinocytes (NHK) and recessive dystrophic epidermolysis bullosa keratinocytes (RDEBK)) and cSCC cell lines are seeded into 96 well plates and live cell number and cell death are

analysed with an IncuCyte ZOOM real-time imager using the CellTox Green Cytotoxicity Assay. Relative EC50 values

are determined using GraphPad Prism. For clonogenic assays cells are seeded into six well plates. Inhibitors (e.g.,

TAK-243; 0.01, 0.1, 1, and 10 μM) are added for the indicated times and then cells are maintained in drug-free

medium for up to 2 weeks to allow colony formation. Colonies are fixed in 10% methanol, 10% acetic acid and

stained with crystal violet[1].

MCE has not independently confirmed the accuracy of these methods. They are for reference only.

Animal Administration [2]Mice[2]

The preclinical efficacy and toxicity of TAK-243 are assessed in mouse models of AML. OCI-AML2 cells are injected subcutaneously (sc) into SCID mice, and when tumors are palpable, mice are treated with TAK-243 (20 mg/kg sc twice weekly). As an additional model, primary AML cells from 2 patients are injected into the femurs of NOD-SCID mice. Two weeks after injection, mice are treated with TAK-243 (20 mg/kg sc twice weekly). After 3 weeks of treatment, mice ae sacrificed, and AML engraftment in the non-injected femur is measured by flow cytometry[2]. MCE has not independently confirmed the accuracy of these methods. They are for reference only.

REFERENCES

[1]. McHugh A, et al. Preclinical comparison of proteasome and ubiquitin E1 enzyme inhibitors in cutaneous squamous cell carcinoma: the identification of mechanisms of differential sensitivity. Oncotarget. 2018 Apr 17;9(29):20265-20281.

[2]. Samir H. Barghout, et al. TAK-243 Is a Selective UBA1 Inhibitor That Displays Preclinical Activity in Acute Myeloid Leukemia (AML). Blood 2017, 130:814.

Caution: Product has not been fully validated for medical applications. For research use only.

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