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

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 IC50 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 EC50 values were significantly higher than in vitro inhibition constants, and the implications of this for exploitation of hFEN1 as a drug target are discussed.

journal_name

Nat Chem Biol

journal_title

Nature chemical biology

authors

Exell JC,Thompson MJ,Finger LD,Shaw SJ,Debreczeni J,Ward TA,McWhirter C,Siöberg CL,Martinez Molina D,Abbott WM,Jones CD,Nissink JW,Durant ST,Grasby JA

doi

10.1038/nchembio.2148

subject

Has Abstract

pub_date

2016-10-01 00:00:00

pages

815-21

issue

10

eissn

1552-4450

issn

1552-4469

pii

nchembio.2148

journal_volume

12

pub_type

杂志文章

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