ArticleScientific reports2019
The MTH1 inhibitor TH588 is a microtubule-modulating agent that eliminates cancer cells by activating the mitotic surveillance pathway.
Article in Scientific reports, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed.
- The MTH1 inhibitor TH287 sensitized Castration-Resistant Prostate Cancer cells to ionizing radiation therapy.International urology and nephrology · 2026Article
- MTH1 in the disorders of the central nervous system: scope beyond brain tumors and challenges.Acta neurologica Belgica · 2025Review
- Article
- Clinical Significance of NUDT1 (MTH1) Across Cancer Types.International journal of molecular sciences · 2025Review
- The multifaceted regulatory roles of Nudix hydrolases in cancer and their therapeutic potential.Frontiers in oncology · 2025Review
- A Collection of Useful Nuisance Compounds (CONS) for Interrogation of Bioassay Integrity.JACS Au · 2024Article
- Coupling cellular drug-target engagement to downstream pharmacology with CeTEAM.Nature communications · 2024Article
- Mitotic MTH1 inhibitor TH1579 induces PD-L1 expression and inflammatory response through the cGAS-STING pathway.Oncogenesis · 2024Article
- Targeting MutT Homolog 1 (MTH1) for Breast Cancer Suppression by Using a Novel MTH1 Inhibitor MA-24 with Tumor-Selective Toxicity.Pharmaceuticals (Basel, Switzerland) · 2024Article
- Mitotic MTH1 Inhibitors in Treatment of Cancer.Cancer treatment and research · 2023Article
- OGG1 competitive inhibitors show important off-target effects by directly inhibiting efflux pumps and disturbing mitotic progression.Frontiers in cell and developmental biology · 2023Article
- Image-Based Annotation of Chemogenomic Libraries for Phenotypic Screening.Molecules (Basel, Switzerland) · 2022Article
- Disrupted mitochondrial homeostasis coupled with mitotic arrest generates antineoplastic oxidative stress.Oncogene · 2022Article
- TH588 and Low-Dose Nocodazole Impair Chromosome Congression by Suppressing Microtubule Turnover within the Mitotic Spindle.Cancers · 2021Article
- Karonudib has potent anti-tumor effects in preclinical models of B-cell lymphoma.Scientific reports · 2021Article
- Targeting human MutT homolog 1 (MTH1) for cancer eradication: current progress and perspectives.Acta pharmaceutica Sinica. B · 2020Review
- Genomic profiling of the transcription factor Zfp148 and its impact on the p53 pathway.Scientific reports · 2020Article
- Intrinsic and Extrinsic Factors Affecting Microtubule Dynamics in Normal and Cancer Cells.Molecules (Basel, Switzerland) · 2020Review
- A high-throughput drug combination screen identifies an anti-glioma synergism between TH588 and PI3K inhibitors.Cancer cell international · 2020Article
Corrections and comments
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Authors and funding
11 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The mut-T homolog-1 (MTH1) inhibitor TH588 has shown promise in preclinical cancer studies but its targeting specificity has been questioned. Alternative mechanisms for the anti-cancer effects of TH588 have been suggested but the question remains unresolved. Here, we performed an unbiased CRISPR screen on human lung cancer cells to identify potential mechanisms behind the cytotoxic effect of TH588. The screen identified pathways and complexes involved in mitotic spindle regulation. Using immunofluorescence and live cell imaging, we showed that TH588 rapidly reduced microtubule plus-end mobility, disrupted mitotic spindles, and prolonged mitosis in a concentration-dependent but MTH1-independent manner. These effects activated a USP28-p53 pathway - the mitotic surveillance pathway - that blocked cell cycle reentry after prolonged mitosis; USP28 acted upstream of p53 to arrest TH588-treated cells in the G1-phase of the cell cycle. We conclude that TH588 is a microtubule-modulating agent that activates the mitotic surveillance pathway and thus prevents cancer cells from re-entering the cell cycle.
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