Last update 01 Nov 2024

MTH1

Last update 01 Nov 2024

Basic Info

Synonyms

2-hydroxy-dATP diphosphatase, 7,8-dihydro-8-oxoguanine triphosphatase, 8-oxo-dGTPase

+ [7]

Introduction

Oxidized purine nucleoside triphosphate hydrolase which is a prominent sanitizer of the oxidized nucleotide pool (PubMed:8226881, PubMed:7713500, PubMed:10608900, PubMed:12857738, PubMed:22556419, PubMed:26238318, PubMed:24695224, PubMed:24695225, PubMed:28679043). Catalyzes the hydrolysis of 2-oxo-dATP (2-hydroxy-dATP) into 2-oxo-dAMP (PubMed:10373420). Has also a significant hydrolase activity toward 2-oxo-ATP, 8-oxo-dGTP and 8-oxo-dATP (PubMed:10373420, PubMed:11139615). Through the hydrolysis of oxidized purine nucleoside triphosphates, prevents their incorporation into DNA and the subsequent transversions A:T to C:G and G:C to T:A (PubMed:8226881, PubMed:10373420, PubMed:10608900, PubMed:11756418, PubMed:12857738, PubMed:16607562, PubMed:24695224, PubMed:24695225, PubMed:26999531, PubMed:28035004). Also catalyzes the hydrolysis of methylated purine nucleoside triphosphate preventing their integration into DNA (PubMed:30304478, PubMed:32144205). Through this antimutagenic activity protects cells from oxidative stress (PubMed:8226881, PubMed:7713500, PubMed:10608900, PubMed:12857738, PubMed:24695224, PubMed:24695225, PubMed:30304478, PubMed:32144205).

Drugs associated with MTH1

Karonudib

Target

MTH1

Mechanism

MTH1 antagonists

Active Org.-

Originator Org.-

Active Indication

Acute Myeloid Leukemia [+1]

Inactive Indication-

Drug Highest PhasePhase 1

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

BAY-707

Target

MTH1

Mechanism

MTH1 antagonists

Active Org.

Bayer AG

Originator Org.

Bayer AG

Active Indication

Neoplasms

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

(S)-crizotinib

Target

MTH1

Mechanism

MTH1 antagonists

Active Org.

Austrian Academy of Sciences

Originator Org.

Austrian Academy of Sciences

Active Indication

Neoplasms

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

Clinical Trials associated with MTH1

NCT04077307 / RecruitingPhase 1IIT

A Phase 1 Study in Patients With Hematological Malignancies to Evaluate Safety, Tolerability and Efficacy of Karonudib

The primary objective of this study is to determine safety and tolerability of Karonudib for the treatment of hematological malignancies.
Secondary objectives are to determine a recommended RP2D and schedule for further development of Karonudib, to determine the pharmacokinetics of Karonudib, to look for evidence of treatment efficacy. Overall survival will also be recorded.

Start Date03 Dec 2019

Sponsor / Collaborator-

NCT03036228 / RecruitingPhase 1IIT

MTH1, A Phase I, Study on Tumors Inhibition, First in Human, First in Class

Primary Objective
• To determine the safety and tolerability of Karonudib (TH1579) in escalating doses for the treatment of patients with advanced solid malignant tumours.
Secondary Objective
To define DLT and MTD.
To determine a recommended phase 2 dose (RP2D) and schedule.
To determine the pharmacokinetics of Karonudib.
To determine preliminary signs of clinical efficacy of Karonudib.
To determine overall survival.

Start Date14 Jan 2017

Sponsor / Collaborator-

100 Clinical Results associated with MTH1

100 Translational Medicine associated with MTH1

0 Patents (Medical) associated with MTH1

570

Literatures (Medical) associated with MTH1

01 Nov 2024·Redox Biology

Role of MTH1 in oxidative stress and therapeutic targeting of cancer

Review

Author: Hassan, Md Imtaiyaz ; Shamsi, Anas ; Rathi, Aanchal ; Hassan, Md. Imtaiyaz ; Taiyab, Aaliya ; Ashraf, Anam ; Sulaimani, Md Nayab

Cancer cells maintain high levels of reactive oxygen species (ROS) to drive their growth, but ROS can trigger cell death through oxidative stress and DNA damage. To survive enhanced ROS levels, cancer cells activate their antioxidant defenses. One such defense is MTH1, an enzyme that prevents the incorporation of oxidized nucleotides into DNA, thus preventing DNA damage and allowing cancer to proliferate. MTH1 levels are often elevated in many cancers, and thus, inhibiting MTH1 is an attractive strategy for suppressing tumor growth and metastasis. Targeted MTH1 inhibition can induce DNA damage in cancer cells, exploiting their vulnerability to oxidative stress and selectively targeting them for destruction. Targeting MTH1 is promising for cancer treatment because normal cells have lower ROS levels and are less dependent on these pathways, making the approach both effective and specific to cancer. This review aims to investigate the potential of MTH1 as a therapeutic target, especially in cancer treatment, offering detailed insights into its structure, function, and role in disease progression. We also discussed various MTH1 inhibitors that have been developed to selectively induce oxidative damage in cancer cells, though their effectiveness varies. In addition, this review provide deeper mechanistic insights into the role of MTH1 in cancer prevention and oxidative stress management in various diseases.

01 Sep 2024·International Journal of Environmental Health Research

Human epithelial lung cell toxicity assessment of collected graphite particles from an iron casting industry (in vitro study)

Article

Author: Panjali, Zahra ; Zendehdel, Rezvan ; Hahad, Omar

Workers in the iron casting industries are exposed to various chemicals, especially graphite in furnace process. This study aims to investigate the toxic effects of graphite particles on human lung cells. Particle characteristics were confirmed by electron microscope and light scattering. Cell viability and oxidative stress markers were measured. The expression of oxidative repair genes, namely OGG1, MTH1, and ITPA, was evaluated. The average particle size was determined to be 172.1 ± 11.96 nm. The median inhibition concentration (IC₅₀) of graphite particles was 46.75 µg/mL. Notably, 25 and 50 µg/mL concentrations resulted in significant GSH depletion and MDA production. The high concentration of graphite particles (200 µg/mL) led to OGG1 suppression and increased MTH1 expression. Based on these findings, graphite exposure may induce toxicity in human lung cells by increasing oxidative stress. Further research is necessary to fully understand the mechanisms underlying graphite toxicity.

01 Sep 2024·Heliyon

Bioinformatics analysis of the role of RNA modification regulators in polycystic ovary syndrome

Article

Author: You, Zilin ; Ning, Shuting ; Quan, Kewei ; Deng, Gaopi

PurposePolycystic ovary syndrome (PCOS) is the most common metabolic and endocrine disorder affecting women of reproductive age. The pathogenesis of PCOS is influenced by factors such as race, genetics, environment, hyperandrogenemia, hyperinsulinemia, and obesity. However, the molecular mechanisms linking RNA modification and PCOS remain underexplored. This study aims to investigate the potential genetic and molecular pathways connecting RNA modification with PCOS through bioinformatics analyses.MethodsThe GSE34526, GSE5850, and GSE98421 datasets were obtained from the National Center for Biotechnology Information Gene Expression Omnibus database. We identified intersecting differentially expressed genes (DEGs) and RNA modification-related genes within the GSE34526 dataset and visualized the overlaps using a Venn diagram. Subsequent analyses included Gene Ontology (GO), pathway enrichment (Kyoto Encyclopedia of Genes and Genomes), gene set enrichment analysis (GSEA), gene set variation analysis (GSVA), and immune infiltration analysis. Additionally, we constructed a protein-protein interaction network as well as mRNA-miRNA, mRNA-RNA binding protein, and mRNA-transcription factor (TF) regulatory networks. The expression and receiver operating characteristic curves of hub genes were also identified.ResultsThe expression of several RNA modification-related DEGs (RMRDEGs) (ALYREF, NUDT1, AGO2, TET2, YTHDF2, and TRMT61B) showed significant differences in PCOS patients. GSEA and GSVA indicated that RMRDEGs were enriched in the hedgehog, MAPK, JAK STAT, and Notch pathways. Key transcription factors, including SP7, KLF8, HCFC1, IRF1, and MLLT1, were identified in the TF regulatory networks.ConclusionsThese findings suggest that there are gene and miRNA profile alterations exist in PCOS patients and highlight immune-related differences. This knowledge could pave the way for new research directions in the diagnosis and treatment of PCOS.

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