TH588

TH588 (1609960-31-7) is a first-in-class nudix hydrolase family inhibitor.1MTH1/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. Activein vitroandin vivo. Recent evidence has raised doubts about the cancer-killing ability of MTH1 inhibition.2,3Conversely, TH588 has been also shown to decrease osteosarcoma cell viability, impair cell cycle, and increase apoptosis via an MTH1-dependent pathway.4

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.

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.

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[1] HELGE GAD. MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool[J]. Nature, 2014, 508 7495: 215-221. DOI:10.1038/nature13181
[2] ALESSIA PETROCCHI. Identification of potent and selective MTH1 inhibitors[J]. Bioorganic & Medicinal Chemistry Letters, 2016, 26 6: Pages 1503-1507. DOI:10.1016/j.bmcl.2016.02.026
[3] JASON G. KETTLE*. Potent and Selective Inhibitors of MTH1 Probe Its Role in Cancer Cell Survival[J]. Journal of Medicinal Chemistry, 2016, 59 6: 2346-2361. DOI:10.1021/acs.jmedchem.5b01760
[4] BRICE MOUKENGUE. TH1579, MTH1 inhibitor, delays tumour growth and inhibits metastases development in osteosarcoma model.[J]. EBioMedicine, 2020, 53: 102704. DOI:10.1016/j.ebiom.2020.102704