7,8-dihydro-8-oxoguanine triphosphatase (MTH1) (MTH1)

7,8-dihydro-8-oxoguanine triphosphatase, commonly known as MTH1 (MutT homolog 1), is a key enzyme in the Nudix hydrolase family responsible for sanitizing the cellular nucleotide pool [8, 10]. 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 during replication [8, 12]. This activity is crucial for maintaining genomic stability, as the incorporation of oxidized nucleotides can lead to transversion mutations and double-strand breaks [12, 17]. In cancer biology, MTH1 is frequently overexpressed to help malignant cells survive the high levels of reactive oxygen species (ROS) generated by their accelerated metabolism and oncogenic signaling [1, 3, 9]. Consequently, MTH1 has emerged as a promising therapeutic target, with inhibitors designed to induce lethal DNA damage specifically in cancer cells while sparing normal cells that have lower oxidative stress [1, 4]. Clinical-stage inhibitors like karonudib (TH1579) are being investigated for their ability to exploit this vulnerability, often in combination with other DNA-damaging agents or antimitotics [2, 6, 11].

Other names

Nudix hydrolase 1NUDT1MutT homolog 18-oxo-dGTPase2-hydroxy-dATP diphosphataseOxidized purine nucleoside triphosphate hydrolase

Inhibition of MTH1 prevents the clearance of oxidized nucleotides from the dNTP pool, leading to their incorporation into DNA, which causes genomic instability, DNA damage, and apoptosis in cancer cells [1, 3, 4].