A non-selective inhibitor of dipeptidyl peptidases
IC50: 1 nM
Talabostat mesilate (PT-100; Val-boroPro) is an orally active, specific inhibitor of dipeptidyl peptidases for DPP4, including tumor-associated fibroblast activation protein- (FAP).
Fibroblast activation protein- (FAP), as an integral membrane serine protease and member of the post-prolyl peptidase family, closely related to dipeptidyl peptidase IV (DPPIV) and displays a DPPIV-like fold with the characteristic /-hydrolase and eightbladed -propeller domains [1].
In vitro: By the cleavage of N-terminal Xaa-Pro or Xaa-Ala residues, talabostat blocks dipeptidyl peptidases, such as fibroblast activation protein (FAP), resulting in inducing the production of cytokine and chemokine (besides specific T-cell immunity and T-cell-dependent activity). This agent may also induce the production of colony stimulating factors, for instance, granulocyte colony stimulating factor (G-CSF), resulting in the inducement of hematopoiesis. Dipeptidyl peptidases are referred to the activation of polypeptide hormones and chemokines.
Talabostat slightly lowered the growth rates of the FAP-expressing tumors but because PT-630 and LAF-237 did not, the growth blockade was likely not related to inhibit FAP or the related post-prolyl peptidase dipeptidyl peptidase IV.[1]
In vivo: So far, no study in vivo has been conducted.
Clinical trial: Clinical study has been conducted.
Reference:
[1].? Huang Y, Simms AE, Mazur A, Wang S, León NR, Jones B, Aziz N, Kelly T. Fibroblast activation protein-α promotes tumor growth and invasion of breast cancer cells through non-enzymatic functions. Clin Exp Metastasis. 2011 Aug;28(6):567-79.
| Cell experiment [1]: | |
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Cell lines |
MDA MB-435 cells and human breast cancer cell lines WTY-1 and WTY-6 |
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Preparation method |
This compound is soluble in DMSO. General tips for obtaining a higher concentration: Please warm the tube at 37 °C for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below - 20 °C for several months. |
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Reacting condition |
10 μM |
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Applications |
In MDA MB-231 cells that do not express FAP, Talabostat showed no effect in FAP activity assay. In WTY-1 and WTY-6 cells that express wild type and active FAP to high levels, Talabostat significantly inhibited FAP activity. |
| Animal experiment [1]: | |
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Animal models |
SCID mice bearing human breast cancer cell lines WTY-1 and WTY-6, as well as MDA MB-435 cells |
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Dosage form |
1.3 mg/kg; p.o.; q.d. |
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Applications |
In SCID mice bearing human breast cancer cell lines WTY-1 and WTY-6, as well as MDA MB-435 cells, Talabostat slightly slowed tumor growth. In mice bearing MDA MB-435 cells, Talabostat delayed production of measurable tumors by nearly 12 days, which however, was not statistically different. |
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Other notes |
Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal. |
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参考文献: [1]. Huang Y, Simms AE, Mazur A, Wang S, León NR, Jones B, Aziz N, Kelly T. Fibroblast activation protein-α promotes tumor growth and invasion of breast cancer cells through non-enzymatic functions. Clin Exp Metastasis. 2011 Aug;28(6):567-79. | |
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