Description
TH588 (1609960-31-7) is a first-in-class nudix hydrolase family inhibitor.1?MTH1/NUDT1 is a family member that “sanitizes” oxidized deoxynucleotide triphosphates (dNTP) preventing their incorporation into DNA and thus avoiding DNA damage and cell death.? TH588 inhibits MTH1/NUDT1 (IC50?= 5 nM) leading to cell death in several cancer cell lines while not affecting normal cells.? Active?in vitro?and?in vivo.? Recent evidence has raised doubts about the cancer-killing ability of MTH1 inhibition.2,3?Conversely, TH588 has been also shown to decrease osteosarcoma cell viability, impair cell cycle, and increase apoptosis via an MTH1-dependent pathway.4
Uses
TH 588 acts as a novel potent and selective permeable inhibitor of the nudix hydrolase MTH1 protein. It acts as a good tool to show the non-oncogene addiction concept to anti-cancer treatments.
Biochem/physiol Actions
TH588 is a potent inhibitor of human 7,8-Dihydro-8-oxoguaninetriphosphatase MTH1 (NUDT1) with an IC50 value of 5 nM and good metabolic stability. MTH1 hydrolyzes oxidized purine nucleoside triphosphates that might otherwise be incorporated into DNA/RNA and contribute to DNA damage. MTH1 removal of oxidized nucleotides that result from increased levels of reactive oxygen species (ROS) in fast-proliferating cancer cells helps protect cancer cells from proliferative stress and prevent cancer cell death. TH588 is considered a new target for cancer therapy. 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 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 vivo
TH588 (30 mg/kg; s.c.; once daily for 35 days) reduces tumour growth in SW480 xenograft cancer model[1].
| Animal Model: | 5-6 weeks female SCID mice (SW480 xenograft cancer model)[1] |
| Dosage: | 30 mg/kg |
| Administration: | Subcutaneous injection; once daily for 35 days |
| Result: | Reduced tumour growth in SW480 xenograft cancer model. |
References
1) Gad?et al. (2014),?MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool; Nature,?508?215
2) Petrocchi et al. (2016)?Identification of potent and selective MTH1 inhibitors; Bioorg. Med. Chem. Lett.,?26?1503
3) Kettle?et al. (2016),?Potent and Selective Inhibitors of MTH1 Probe Its Role in Cancer Cell Survival; J. Med. Chem.,?59?2346
4) Moukengue?et al. (2020),?TH1579, MTH1 inhibitor, delays tumour growth and inhibits metastases development in osteosarcoma model; EBioMedicine,?53?102704
