Background:

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.