N-Hydroxyimides and hydroxypyrimidinones as inhibitors of the DNA repair complex ERCC1-XPF

Timothy M. Chapman; Claire Wallace; Kevin J. Gillen; Preeti Bakrania; Puneet Khurana; Peter J. Coombs; Simon Fox; Emilie A. Bureau; Janet Brownlees; David Melton; Barbara Saxty

doi:doi:10.1016/j.bmcl.2015.08.024

N-Hydroxyimides and hydroxypyrimidinones as inhibitors of the DNA repair complex ERCC1-XPF

Timothy M. Chapman, Claire Wallace, Kevin J. Gillen, Preeti Bakrania, Puneet Khurana, Peter J. Coombs, Simon Fox, Emilie A. Bureau, Janet Brownlees, David Melton, Barbara Saxty

Research output: Contribution to journal › Article › peer-review

Abstract

A high throughput screen allowed the identification of N-hydroxyimide inhibitors of ERCC1-XPF endonuclease activity with micromolar potency, but they showed undesirable selectivity profiles against FEN-1. A scaffold hop to a hydroxypyrimidinone template gave compounds with similar potency but allowed selectivity to be switched in favour of ERCC1-XPF over FEN-1. Further exploration of the structure-activity relationships around this chemotype gave sub-micromolar inhibitors with >10-fold selectivity for ERCC1-XPF over FEN-1.

Original language	English
Journal	Bioorganic & Medicinal Chemistry Letters
Volume	25
Issue number	19
Early online date	14 Aug 2015
DOIs	https://doi.org/doi:10.1016/j.bmcl.2015.08.024
Publication status	Published - 1 Oct 2015

Keywords

DNA Repair
ERCC1-XPF
N-Hydroxyimide
Hydroxypyrimidinone

Access to Document

doi:10.1016/j.bmcl.2015.08.024

Chapman_submission_2_main_R1
This is the final author's manuscript as accepted for publication.
Accepted author manuscript, 128 KBLicence: Creative Commons: Attribution-NonCommercial-NoDerivatives (CC BY-NC-ND)

http://www.sciencedirect.com/science/article/pii/S0960894X15008598

Cite this

@article{fc64433e6f8741ce8ca4ec66c888c17b,

title = "N-Hydroxyimides and hydroxypyrimidinones as inhibitors of the DNA repair complex ERCC1-XPF",

abstract = "A high throughput screen allowed the identification of N-hydroxyimide inhibitors of ERCC1-XPF endonuclease activity with micromolar potency, but they showed undesirable selectivity profiles against FEN-1. A scaffold hop to a hydroxypyrimidinone template gave compounds with similar potency but allowed selectivity to be switched in favour of ERCC1-XPF over FEN-1. Further exploration of the structure-activity relationships around this chemotype gave sub-micromolar inhibitors with >10-fold selectivity for ERCC1-XPF over FEN-1.",

keywords = "DNA Repair, ERCC1-XPF, N-Hydroxyimide, Hydroxypyrimidinone",

author = "Chapman, {Timothy M.} and Claire Wallace and Gillen, {Kevin J.} and Preeti Bakrania and Puneet Khurana and Coombs, {Peter J.} and Simon Fox and Bureau, {Emilie A.} and Janet Brownlees and David Melton and Barbara Saxty",

year = "2015",

month = oct,

day = "1",

doi = "doi:10.1016/j.bmcl.2015.08.024",

language = "English",

volume = "25",

journal = "Bioorganic & Medicinal Chemistry Letters",

issn = "0960-894X",

publisher = "Elsevier Limited",

number = "19",

}

N-Hydroxyimides and hydroxypyrimidinones as inhibitors of the DNA repair complex ERCC1-XPF. / Chapman, Timothy M.; Wallace, Claire; Gillen, Kevin J.; Bakrania, Preeti; Khurana, Puneet; Coombs, Peter J.; Fox, Simon; Bureau, Emilie A.; Brownlees, Janet; Melton, David; Saxty, Barbara.

In: Bioorganic & Medicinal Chemistry Letters, Vol. 25, No. 19, 01.10.2015.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - N-Hydroxyimides and hydroxypyrimidinones as inhibitors of the DNA repair complex ERCC1-XPF

AU - Chapman, Timothy M.

AU - Wallace, Claire

AU - Gillen, Kevin J.

AU - Bakrania, Preeti

AU - Khurana, Puneet

AU - Coombs, Peter J.

AU - Fox, Simon

AU - Bureau, Emilie A.

AU - Brownlees, Janet

AU - Melton, David

AU - Saxty, Barbara

PY - 2015/10/1

Y1 - 2015/10/1

N2 - A high throughput screen allowed the identification of N-hydroxyimide inhibitors of ERCC1-XPF endonuclease activity with micromolar potency, but they showed undesirable selectivity profiles against FEN-1. A scaffold hop to a hydroxypyrimidinone template gave compounds with similar potency but allowed selectivity to be switched in favour of ERCC1-XPF over FEN-1. Further exploration of the structure-activity relationships around this chemotype gave sub-micromolar inhibitors with >10-fold selectivity for ERCC1-XPF over FEN-1.

AB - A high throughput screen allowed the identification of N-hydroxyimide inhibitors of ERCC1-XPF endonuclease activity with micromolar potency, but they showed undesirable selectivity profiles against FEN-1. A scaffold hop to a hydroxypyrimidinone template gave compounds with similar potency but allowed selectivity to be switched in favour of ERCC1-XPF over FEN-1. Further exploration of the structure-activity relationships around this chemotype gave sub-micromolar inhibitors with >10-fold selectivity for ERCC1-XPF over FEN-1.

KW - DNA Repair

KW - ERCC1-XPF

KW - N-Hydroxyimide

KW - Hydroxypyrimidinone

U2 - doi:10.1016/j.bmcl.2015.08.024

DO - doi:10.1016/j.bmcl.2015.08.024

M3 - Article

VL - 25

JO - Bioorganic & Medicinal Chemistry Letters

JF - Bioorganic & Medicinal Chemistry Letters

SN - 0960-894X

IS - 19

ER -

N-Hydroxyimides and hydroxypyrimidinones as inhibitors of the DNA repair complex ERCC1-XPF

Abstract

Keywords

Access to Document

Fingerprint

Cite this