Contaminating cancer genomes

Two European teams have pinpointed the DNA-protective enzyme 7,8-dihydro-8-oxoguanine triphosphatase as a chemically tractable target whose inhibition kills cancer cells by accelerating DNA damage.1,2 Both groups have identified collections of small molecule inhibitors of the enzyme-one of which is an isomer of cancer drug Xalkori crizotinib-and both are looking to partner with industry.

The compounds could be useful to treat a range of tumor types, including K-Ras (KRAS)-mutant cancers.

The normal role of 7,8-dihydro-8-oxoguanine triphosphatase (NUDT1; MTH1) is to prevent DNA damage by cleaving oxidized dATP or dGTP, which can accumulate and inappropriately incorporate into the genome if left unchecked.

Recent studies have shown that MTH1 is overexpressed in Ras-dependent cancers and can suppress oxidative damage. That finding suggested that inhibiting the target could be lethal to tumor cells.3

Thomas Helleday, a professor at the Karolinska Institute, became interested in MTH1 in cancer based in part on these earlier

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