1. Protein Tyrosine Kinase/RTK
  2. PDGFR

TSU-68 (Synonyms: SU6668)

Cat. No.: HY-10517 Purity: 99.02%
Data Sheet SDS Handling Instructions

TSU-68 is a novel multiple receptor tyrosine kinase inhibitor with IC50 of 2.1 μM, 8 nM and 1.2 μM for VEGF-R1, PDGF-Rβ and FGF-R1, respectively, and has greatest potency against PDGFR autophosphorylation.

For research use only. We do not sell to patients.
TSU-68 Chemical Structure

TSU-68 Chemical Structure

CAS No. : 252916-29-3

Size Price Stock Quantity
10 mM * 1 mL in DMSO $99 In-stock
10 mg $90 In-stock
50 mg $360 In-stock
100 mg $630 In-stock
200 mg   Get quote  
500 mg   Get quote  

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  • Biological Activity

  • Protocol

  • Technical Information

  • Purity & Documentation

  • References

Description

TSU-68 is a novel multiple receptor tyrosine kinase inhibitor with IC50 of 2.1 μM, 8 nM and 1.2 μM for VEGF-R1, PDGF-Rβ and FGF-R1, respectively, and has greatest potency against PDGFR autophosphorylation.

IC50 & Target

IC50: 8 nM (PDGF-Rβ)

In Vitro

TSU-68 is a competitive inhibitor, with regard to ATP, to Flk-1/KDR trans-phosphorylation, FGFR1 trans-phosphorylation, and PDGFRβ kinases autophosphorylation. TSU-68 (0.03-10 μM) inhibits tyrosine phosphorylation of KDR in VEGF stimulated HUVECs. TSU-68 also inhibits PDGF-stimulated PDGFRβ tyrosine phosphorylation in NIH-3T3 cells overexpressing PDGFRβ at a minimum concentration of 0.03-0.1 μM. TSU-68 inhibits acidic FGF-induced phosphorylation of the FGFR1 substrate 2 at 10 μM and higher. However, TSU-68 (up to 100 μM) has no effect on EGF-stimulated EGFR tyrosine phosphorylation in NIH-3T3 cells overexpressing EGFR. TSU-68 inhibits VEGF-driven and FGF-driven mitogenesis of HUVECs with mean IC50 of 0.34 μM and 9.6 μM, respectively[1]. In human myeloid leukemia MO7E cells, TSU-68 inhibits the tyrosine autophosphorylation of stem cell factor (SCF) receptor, c-kit, with IC50 of 0.1-1 μM, as well as ERK1/2 phosphorylation, a signaling event downstream of c-kit activation. TSU-68 also inhibits SCF-induced proliferation of MO7E cells with IC50 of 0.29 μM, and induces apoptosis[2].

In Vivo

TSU-68 (75-200 mg/kg) induces tumor growth inhibition against a broad range of tumor types in xenograft models in athymic mice, including A375, Colo205, H460, Calu-6, C6, SF763T, and SKOV3TP5 cells. TSU-68 (75 mg/kg) also suppresses tumor angiogenesis of C6 glioma xenografts[1]. In a tumor model of HT29 human colon carcinoma, TSU-68 (200 mg/kg) decreases the average vessel permeability and average fractional plasma volume in the tumor rim and core. TSU-68 promotes abnormal stromal development at the periphery of carcinomas[3]. TSU-68 (200 mg/kg) augments the effect of chemotherapeutic infusion in a rabbit VX2 liver tumor model[4].

Clinical Trial
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References
Preparing Stock Solutions
Concentration Volume Mass 1 mg 5 mg 10 mg
1 mM 3.2222 mL 16.1108 mL 32.2217 mL
5 mM 0.6444 mL 3.2222 mL 6.4443 mL
10 mM 0.3222 mL 1.6111 mL 3.2222 mL
Please refer to the solubility information to select the appropriate solvent.
Kinase Assay
[1]

Tyrosine kinase assays to quantitate the trans-phosphorylation activity of Flk-1 and FGFR1 are performed in 96-well microtiter plates precoated (20 μg/well in PBS; incubated overnight at 4°C) with the peptide substrate poly-Glu,Tyr (4:1). Excess protein binding sites are blocked with 1-5% (w/v) BSA in PBS. Purified GST-FGFR1 (kinase domain) or GST-Flk-1 (cytoplasmic domain) fusion proteins are then added to the microtiter wells in 2× concentration kinase dilution buffer consisting of 100 mM HEPES, 50 mM NaCl, 40 μM NaVO4, and 0.02% (w/v) BSA. The final enzyme concentration for GST-Flk-1 and GST-FGFR1 is 50 ng/mL. SU6668 is dissolved in DMSO at 100× the final required concentration and diluted 1:25 in H2O. Twenty-five μL of diluted SU6668 are subsequently added to each reaction well. The kinase reaction is initiated by the addition of different concentrations of ATP in a solution of MnCl2 so that the final ATP concentrations spans the Km for the enzyme, and the final concentration of MnCl2 is 10 mM. The plates are incubated for 5-15 min at room temperature before stopping the reaction with the addition of EDTA. The plates are then washed three times with TBST. Rabbit polyclonal antiphosphotyrosine antisera are added to the wells at a 1: 10000 dilution in TBST containing 0.5% (w/v) BSA, 0.025% (w/v) nonfat dry milk, and 100 μM NaVO4 and incubated for 1 hour at 37°C. The plates are then washed three times with TBST, followed by the addition of goat anti-rabbit antisera conjugated with HRP. The plates are incubated for 1 hour at 37°C and then washed three times with TBST. MCE has not independently confirmed the accuracy of these methods. They are for reference only.

Cell Assay
[1]

Cells are seeded (3×105 cells/35-mm well) in DMEM containing 10% (v/v) FBS and grow to confluence and then quiesced in DMEM containing 0.1% serum for 2 hours before drug treatment. HUVECs (seeded at 2×106 cells/10-cm plate) are grown to confluence in endothelial cell growth media and then quiesced in endothelial cell basal media containing 0.5% FBS for 24 hours before drug treatment. All cell lines are incubated with SU6668 for 1 hour before ligand stimulation (100 ng/mL) for 10 min. MCE has not independently confirmed the accuracy of these methods. They are for reference only.

Animal Administration
[1]

SU6668 is dissolved in DMSO for i.p. administration; SU6668 is suspended in a cremophor-based vehicle for p.o. administration.

Colo205 and H460 cells are cultured in RPMI 1640 supplemented with 10% FBS and 2 mm glutamine. SKOV3 cells are passaged five times through mice to yield SKOV3TP5 cells. These cells are cultured in DMEM supplemented with 10% FBS and 2 mm glutamine. Tumor cells (3-10×106 cells/animal) are implanted s.c. into the hind flank of mice on day 0. Daily treatment with SU6668 or vehicle commenced 1 day after implantation of cells (to test efficacy against newly implanted tumors) or when tumors have reached a predetermined average size (to test efficacy against established tumors). SU6668 is delivered i.p. by bolus injection in DMSO or p.o. by gavage in a cremophor-based vehicle according to the specifics stated in figure and table legends. Tumor growth is measured twice a week using vernier calipers for the duration of treatment. Tumor volumes are calculated as a product of length × width × height. MCE has not independently confirmed the accuracy of these methods. They are for reference only.

References
Molecular Weight

310.35

Formula

C₁₈H₁₈N₂O₃

CAS No.

252916-29-3

Storage
Powder -20°C 3 years
  4°C 2 years
In solvent -80°C 6 months
  -20°C 1 month
Shipping

Room temperature in continental US; may vary elsewhere

Solvent & Solubility

DMSO: ≥ 28 mg/mL

* "<1 mg/mL" means slightly soluble or insoluble. "≥" means soluble, but saturation unknown.

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TSU-68
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