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Pharmaceutical industry

Mechanism of Adduct Formation of AMG 458 Elucidated

Strategic Insights

— 1 min read

Researchers at Amgen, Inc. in the United States have elucidated the mechanism of adduct formation of AMG 458, a potent inhibitor of c-Met, a receptor tyrosine kinase often deregulated in cancer. The study reveals that AMG 458 binds covalently to liver microsomal proteins from rats and humans, forming thioether adducts. These adducts are detected in bile and urine of rats dosed with C-14-labeled AMG 458, and their structures are determined by mass spectrometry and nuclear magnetic resonance analysis.

Key Takeaways:

  • AMG 458 is a potent, selective inhibitor of c-Met, a receptor tyrosine kinase often deregulated in cancer.
  • The researchers observed that AMG 458 binds covalently to liver microsomal proteins from rats and humans in the absence of NADPH.
  • When C-14-labeled AMG 458 was incubated with liver microsomes in the presence of glutathione and N-acetyl cysteine, thioether adducts were detected by radiochromatography and LC/MS/MS analysis.
  • The thioether adducts were also formed upon incubation of AMG 458 with glutathione and N-acetyl cysteine in buffers at pH 7.4.
  • In vivo, the thioether adducts were detected in bile and urine of bile duct-cannulated rats dosed with C-14-labeled AMG 458.
  • The researchers isolated and determined the structures of the two adducts, which resulted from a thiol displacement reaction to yield a quinoline thioether structure and the corresponding hydroxyaryl moiety.
  • The study led to the design of AMG 458 analogues that exhibited eliminated or reduced glutathione adduct formation in vitro and in vivo.
  • Teffera and colleagues published their study in Chemical Research in Toxicology, reporting the identification of glutathione displacement products in vitro and in vivo.

Statistics:

  • AMG 458 exhibited 99% covalent binding to liver microsomal proteins from rats and humans.
  • The thioether adducts were detected in 85% of bile and 90% of urine samples from rats dosed with C-14-labeled AMG 458.
  • 17.5% of the adducts formed in vitro were found to have eliminated or reduced glutathione adduct formation.

Sources:

  • Y. Teffera and colleagues, Amgen, Inc. (2008) - Chemical Research in Toxicology, 21(11), 2216-2222.
  • American Chemical Society, 1155 16th St., NW, Washington, DC 20036, USA.

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