TH588

MTH1 inhibitor CAS# 1609960-31-7

TH588

2D Structure

Catalog No. BCC6397----Order now to get a substantial discount!

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TH588

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Chemical Properties of TH588

Cas No. 1609960-31-7 SDF Download SDF
PubChem ID 73389731 Appearance Powder
Formula C13H12Cl2N4 M.Wt 295.17
Type of Compound N/A Storage Desiccate at -20°C
Solubility DMSO : 16 mg/mL (54.21 mM; Need ultrasonic and warming)
Chemical Name 4-N-cyclopropyl-6-(2,3-dichlorophenyl)pyrimidine-2,4-diamine
SMILES C1CC1NC2=NC(=NC(=C2)C3=C(C(=CC=C3)Cl)Cl)N
Standard InChIKey PNMYJIOQIAEYQL-UHFFFAOYSA-N
Standard InChI InChI=1S/C13H12Cl2N4/c14-9-3-1-2-8(12(9)15)10-6-11(17-7-4-5-7)19-13(16)18-10/h1-3,6-7H,4-5H2,(H3,16,17,18,19)
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of TH588

DescriptionPotent MTH1 inhibitor (IC50 = 5 nM). Induces oxidative DNA damage and reduces survival in cancer cells. Inhibits growth of breast and colorectal cancer xenografts in mice.

TH588 Dilution Calculator

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TH588 Molarity Calculator

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Preparing Stock Solutions of TH588

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 3.3879 mL 16.9394 mL 33.8788 mL 67.7576 mL 84.697 mL
5 mM 0.6776 mL 3.3879 mL 6.7758 mL 13.5515 mL 16.9394 mL
10 mM 0.3388 mL 1.6939 mL 3.3879 mL 6.7758 mL 8.4697 mL
50 mM 0.0678 mL 0.3388 mL 0.6776 mL 1.3552 mL 1.6939 mL
100 mM 0.0339 mL 0.1694 mL 0.3388 mL 0.6776 mL 0.847 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

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Background on TH588

TH588 is a potent and selective MTH1 inhibitor (IC50 = 5 nM).

MTH1 (human MutT homolog 1) is an antimutagenic purine nucleoside triphosphatase that sanitize oxidized nucleotide pools. It’s a new cancer therapeutic target as it protects the cancer cell from DNA damages such as oxidative stress-induced cell dysfunction or death.

In U2OS and other cancer cell lines, TH588 treatment selectively and effectively kill cancer cells with less toxic to some primary or immortalized cells. U2OS cells treated with TH588 shows increase of 8-oxodG in DNA. The MTH1 inhibitor TH588 induces DNA damage and activates an ATM-p53-mediated death response and DNA repair in U2OS cells. [1]

Mice were transplanted with BRAFV600E-mutated melanoma, resistant to carboplatin, dacarbazine and vemurafenib. Ten of the tumor mice were randomized to receive TH588 once daily or vehicle control treatment. All TH588-treated mice had a reduced tumor growth rate, although the serum amount of TH588 decreased below IC50 concentrations during 24 hours treatment. [1]

Reference:
1.  Gad H, Koolmeister T, Jemth AS et al. MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool. Nature. 2014 Apr 10;508(7495):215-21.

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References on TH588

Development and validation of method for TH588 and TH287, potent MTH1 inhibitors and new anti-cancer agents, for pharmacokinetic studies in mice plasma.[Pubmed:25459754]

J Pharm Biomed Anal. 2015 Feb;104:1-11.

MTH1 is a protein that is required for cancer cell survival and is overexpressed in cancer cells. TH588 and TH287 are two new compounds that inhibit the MTH1 protein. The inhibitors were tested in pharmacokinetic studies on mice. A bioanalytical method was developed and validated for determination in mice plasma. The method was based on protein precipitation followed by LC-MS/MS analysis. The separation was performed on an Ascentis Express RP-Amide C18 column. The mass spectrometer was operated in positive electrospray ionization mode and the analytes were determined with multiple reaction monitoring (MRM). Abundant monoisotopic fragments were used for quantification. Two additional fragments were used for conformational analysis. The recovery of the compounds in plasma varied between 61 and 91% and the matrix effects were low and ranged between -3% and +2%. The method showed to be selective, linear, accurate and precise, and applicable for preclinical pharmacokinetic studies of TH588 and TH287 in mouse plasma. Half-life (T1/2) was

Reactive Oxygen Species Dictate the Apoptotic Response of Melanoma Cells to TH588.[Pubmed:27427486]

J Invest Dermatol. 2016 Nov;136(11):2277-2286.

The effect of MTH1 inhibition on cancer cell survival has been elusive. Here we report that although silencing of MTH1 does not affect survival of melanoma cells, TH588, one of the first-in-class MTH1 inhibitors, kills melanoma cells through apoptosis independently of its inhibitory effect on MTH1. Induction of apoptosis by TH588 was not alleviated by MTH1 overexpression or introduction of the bacterial homolog of MTH1 that has 8-oxodGTPase activity but cannot be inhibited by TH588, indicating that MTH1 inhibition is not the cause of TH588-induced killing of melanoma cells. Although knockdown of MTH1 did not impinge on the viability of melanoma cells, it rendered melanoma cells sensitive to apoptosis induced by the oxidative stress inducer elesclomol. Of note, treatment with elesclomol also enhanced TH588-induced apoptosis, whereas a reactive oxygen species scavenger or an antioxidant attenuated the apoptosis triggered by TH588. Indeed, the sensitivity of melanoma cells to TH588 was correlated with endogenous levels of reactive oxygen species. Collectively, these results indicate that the cytotoxicity of TH588 toward melanoma cells is not associated with its inhibitory effect on MTH1, although it is mediated by cellular production of ROS.

Description

TH588 is first-in-class nudix hydrolase family inhibitor that potently and selectively engage and inhibit the MTH1 (IC50= 5 nM).

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