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TH588 a first-in-class nudix hydrolase family inhibitor that potently and selectively engages and inhibits the MTH1 protein in cells. Protein co-crystal structures demonstrate that the inhibitor binds in the active site of MTH1.
MTH1 inhibitor TH588 is highly selective towards MTH1, with no relevant inhibition of other members of the nudix protein family or a panel of 87 enzymes, GPCRs, kinases, ion channels and transporter. TH588 also induces DNA damage and triggers an ATM-p53-mediated death response and DNA repair in U2OS cells. TH588 has been shown to selectively kill a variety of cancer cell lines and with in vivo activity shown for TH588 in SW480 colorectal and MCF7 breast tumour xenografts.
In mice bearing SW480 colorectal or MCF7 breast tumor xenografts, TH588 (30 mg/kg s.c.) reduces tumor growth via MTH1 inhibition. In mice carrying patient with BRAFV600E mutated xenografts, TH588 (30 mg/kg s.c.) also causes a reduced tumor growth rate.
| Cell Experiment | |
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| Cell lines | |
| Preparation method | |
| Concentrations | |
| Incubation time | |
| Animal Experiment | |
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| Animal models | SCID mice bearing SW480 xenografts or MCF-7 xenografts; NOD-SCID IL2Rγnull (NOG) mice bearing patient with BRAFV600E mutated xenografts |
| Formulation | 2% DMSO, 10% ethanol, 10% cremaphore, 10% Tween 80, 68% PBS; 10% N-methylpyrrilidone, 90% PEG300 |
| Dosages | 30 mg/kg, once daily |
| Administration | s.c. |
| Molecular Weight | 295.17 |
| Formula | C13H12Cl2N4 |
| CAS Number | 1609960-31-7 |
| Solubility (25°C) | DMSO 18 mg/mL warmed |
| Storage |
Powder -20°C 3 years ; 4°C 2 years In solvent -80°C 6 months ; -20°C 1 month |
| Related MTH1 Products |
|---|
| (S)-crizotinib
(S)-crizotinib, the (S)-enantiomer of crizotinib, is a potent MTH1 (NUDT1) inhibitor with IC50 of 72 nM. |
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