7,8-Dihydro-8-oxoguanine triphosphatase (NUDT1;
In vitro, cell culture and mouse studies have identified
inhibitors of MTH1 that could help treat cancer. MTH1 cleaves and neutralizes
oxidized nucleotides, which can accumulate and cause DNA damage. In cancer
cell lines, shRNA against MTH1 induced cell death, whereas control
shRNA did not. In cell lines, a series of small molecule MTH1 inhibitors,
including the (S) stereoisomer of Xalkori
inhibited MTH1 with nanomolar potency, induced DNA damage and killed cancer
cells at micromolar concentrations without also killing untransformed cells.
In multiple mouse models of cancer, including Ras-mutant
cancers, the inhibitors decreased tumor growth compared with vehicle. Next
steps include optimizing compounds for additional preclinical testing.
Pfizer Inc. markets the c-Met
receptor tyrosine kinase and anaplastic
lymphoma kinase (ALK)
inhibitor Xalkori, the (R) stereoisomer of crizotinib, to treat ALK
fusion-positive non-small cell lung cancer (NSCLC).
Published online April 24, 2014
Patent applications filed
for both studies; available for licensing
Huber, K.V.M. et al.
Nature; published online April 2, 2014;
Contact: Giulio Superti-Furga, Research Center for Molecular
Medicine of the Austrian Academy of Sciences, Vienna, Austria
Gad, H. et al. Nature; published online April 2, 2014;
Contact: Thomas Helleday, Karolinska Institute, Stockholm,