Potent and Selective Inhibitors of MTH1 Probe Its Role in Cancer Cell Survival

Recent
literature has claimed that inhibition of the enzyme MTH1 can eradicate
cancer. MTH1 is one of the “housekeeping” enzymes that
are responsible for hydrolyzing damaged nucleotides in cells and thus
prevent them from being incorporated into DNA. We have developed orthogonal
and chemically distinct tool compounds to those published in the literature
to allow us to test the hypothesis that inhibition of MTH1 has wide
applicability in the treatment of cancer. Here we present the work
that led to the discovery of three structurally different series of
MTH1 inhibitors with excellent potency, selectivity, and proven target
engagement in cells. None of these compounds elicited the reported
cellular phenotype, and additional siRNA and CRISPR experiments further
support these observations. Critically, the difference between the
responses of our highly selective inhibitors and published tool compounds
suggests that the effect reported for the latter may be due to off-target
cytotoxic effects. As a result, we conclude that the role of MTH1
in carcinogenesis and utility of its inhibition is yet to be established.