An organometallic inhibitor for the human repair enzyme 7,8-dihydro-8-oxoguanosine triphosphatase

Angew Chem Int Ed Engl. 2014 Jan 3;53(1):305-9. doi: 10.1002/anie.201307849. Epub 2013 Nov 20.

Abstract

The probe-based discovery of the first small-molecule inhibitor of the repair enzyme 8-oxo-dGTPase (MTH1) is presented, which is an unconventional cyclometalated ruthenium half-sandwich complex. The organometallic inhibitor with low-nanomolar activity displays astonishing specificity, as verified in tests with an extended panel of protein kinases and other ATP binding proteins. The binding of the organometallic inhibitor to MTH1 is investigated by protein crystallography.

Keywords: 7,8-dihydro-8-oxoguanosine triphosphatase; enzyme inhibitors; organometallic compounds; protein crystal structures; ruthenium.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • DNA Repair Enzymes / chemistry*
  • DNA Repair Enzymes / pharmacology
  • Humans
  • Organometallic Compounds / chemistry
  • Organometallic Compounds / pharmacology
  • Phosphoric Monoester Hydrolases / chemistry*
  • Phosphoric Monoester Hydrolases / pharmacology
  • Ruthenium / chemistry*

Substances

  • Organometallic Compounds
  • Ruthenium
  • Phosphoric Monoester Hydrolases
  • 8-oxodGTPase
  • DNA Repair Enzymes