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Cellularly active N-hydroxyurea FEN1 inhibitors block substrate entry to the active site

Research output: Contribution to journalReview article

Published
  • Jack C. Exell
  • Mark J. Thompson
  • L. David Finger
  • Steven J. Shaw
  • Judit Debreczeni
  • Thomas A. Ward
  • Claire McWhirter
  • Catrine L.B. Siöberg
  • Daniel Martinez Molina
  • W. Mark Abbott
  • Clifford D. Jones
  • J. Willem M. Nissink
  • Stephen T. Durant
  • Jane A. Grasby
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<mark>Journal publication date</mark>10/2016
<mark>Journal</mark>Nature Chemical Biology
Issue number10
Volume12
Number of pages7
Pages (from-to)815-821
Publication StatusPublished
Early online date15/08/16
<mark>Original language</mark>English

Abstract

The structure-specific nuclease human flap endonuclease-1 (hFEN1) plays a key role in DNA replication and repair and may be of interest as an oncology target. We present the crystal structure of inhibitor-bound hFEN1, which shows a cyclic N-hydroxyurea bound in the active site coordinated to two magnesium ions. Three such compounds had similar IC 50 values but differed subtly in mode of action. One had comparable affinity for protein and protein-substrate complex and prevented reaction by binding to active site catalytic metal ions, blocking the necessary unpairing of substrate DNA. Other compounds were more competitive with substrate. Cellular thermal shift data showed that both inhibitor types engaged with hFEN1 in cells, and activation of the DNA damage response was evident upon treatment with inhibitors. However, cellular EC 50 values were significantly higher than in vitro inhibition constants, and the implications of this for exploitation of hFEN1 as a drug target are discussed.