MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool

Nature. 2014 Apr 10;508(7495):215-21. doi: 10.1038/nature13181. Epub 2014 Apr 2.

Abstract

Cancers have dysfunctional redox regulation resulting in reactive oxygen species production, damaging both DNA and free dNTPs. The MTH1 protein sanitizes oxidized dNTP pools to prevent incorporation of damaged bases during DNA replication. Although MTH1 is non-essential in normal cells, we show that cancer cells require MTH1 activity to avoid incorporation of oxidized dNTPs, resulting in DNA damage and cell death. We validate MTH1 as an anticancer target in vivo and describe small molecules TH287 and TH588 as first-in-class nudix hydrolase family inhibitors that potently and selectively engage and inhibit the MTH1 protein in cells. Protein co-crystal structures demonstrate that the inhibitors bind in the active site of MTH1. The inhibitors cause incorporation of oxidized dNTPs in cancer cells, leading to DNA damage, cytotoxicity and therapeutic responses in patient-derived mouse xenografts. This study exemplifies the non-oncogene addiction concept for anticancer treatment and validates MTH1 as being cancer phenotypic lethal.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Catalytic Domain
  • Cell Death / drug effects
  • Cell Survival / drug effects
  • Crystallization
  • DNA Damage
  • DNA Repair Enzymes / antagonists & inhibitors*
  • DNA Repair Enzymes / chemistry
  • DNA Repair Enzymes / metabolism
  • Deoxyguanine Nucleotides / metabolism
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacokinetics
  • Enzyme Inhibitors / pharmacology
  • Enzyme Inhibitors / therapeutic use
  • Female
  • Humans
  • Male
  • Mice
  • Models, Molecular
  • Molecular Conformation
  • Molecular Targeted Therapy
  • Neoplasms / drug therapy*
  • Neoplasms / metabolism*
  • Neoplasms / pathology
  • Nucleotides / metabolism*
  • Oxidation-Reduction / drug effects
  • Phosphoric Monoester Hydrolases / antagonists & inhibitors*
  • Phosphoric Monoester Hydrolases / chemistry
  • Phosphoric Monoester Hydrolases / metabolism
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacokinetics
  • Pyrimidines / pharmacology
  • Pyrimidines / therapeutic use
  • Pyrophosphatases / antagonists & inhibitors
  • Reproducibility of Results
  • Xenograft Model Antitumor Assays

Substances

  • Deoxyguanine Nucleotides
  • Enzyme Inhibitors
  • Nucleotides
  • Pyrimidines
  • TH287 compound
  • TH588 compound
  • 8-oxodeoxyguanosine triphosphate
  • Phosphoric Monoester Hydrolases
  • Pyrophosphatases
  • nudix hydrolases
  • 8-oxodGTPase
  • DNA Repair Enzymes