Nudix hydrolase 1 (MTH1) (MTH1)

Nudix hydrolase 1 (MTH1), also known as MutT homolog 1, is a critical enzyme responsible for maintaining genomic integrity by sanitizing the cellular nucleotide pool. It functions by hydrolyzing oxidized purine nucleoside triphosphates, such as 8-oxo-dGTP and 2-hydroxy-dATP, into their corresponding monophosphates, thereby preventing their misincorporation into DNA and RNA during replication and transcription. This activity is essential for preventing transversion mutations and protecting cells from oxidative stress-induced damage. In many cancers, MTH1 is significantly overexpressed to help malignant cells survive the high levels of reactive oxygen species (ROS) characteristic of the tumor environment, a phenomenon known as non-oncogene addiction. Consequently, MTH1 has been pursued as a therapeutic target, with small-molecule inhibitors like TH588 and the clinical candidate karonudib (TH1579) designed to induce lethal DNA damage specifically in cancer cells. However, the validity of MTH1 as a target has been debated, as some studies suggest that the anti-tumor effects of certain inhibitors may arise from off-target activities, such as microtubule disruption, rather than MTH1 inhibition alone. Despite these controversies, MTH1 continues to be investigated as a potential biomarker and a target for novel anticancer strategies in various malignancies and neurodegenerative conditions.

Other names

MutT homolog 17,8-dihydro-8-oxoguanine triphosphatase8-oxo-dGTPase2-hydroxy-dATP diphosphataseNucleoside diphosphate-linked moiety X motif 1Nudix motif 1NUDT1

MTH1 inhibitors block the enzymatic activity of Nudix hydrolase 1, preventing the sanitization of oxidized nucleotide pools (e.g., 8-oxo-dGTP). This leads to the incorporation of damaged nucleotides into DNA, resulting in double-strand breaks, genomic instability, and selective apoptosis in cancer cells, which often exhibit high oxidative stress.