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Citation

BibTex format

@article{Howard:2020:10.1021/acschembio.9b00963,
author = {Howard, RT and Hemsley, P and Petteruti, P and Saunders, CN and Molina, Bermejo JA and Scott, JS and Johannes, JW and Tate, EW},
doi = {10.1021/acschembio.9b00963},
journal = {ACS Chemical Biology},
pages = {325--333},
title = {Structure-guided design and in-cell target profiling of a cell-active target engagement probe for PARP inhibitors},
url = {http://dx.doi.org/10.1021/acschembio.9b00963},
volume = {15},
year = {2020}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - Inhibition of the poly(ADP-ribose) polymerase (PARP) family of enzymes has become an attractive therapeutic strategy in oncology and beyond; however, chemical tools to profile PARP engagement in live cells are lacking. Herein, we report the design and application of PARPYnD, the first photoaffinity probe (AfBP) for PARP enzymes based on triple PARP1/2/6 inhibitor AZ9482, which induces multipolar spindle (MPS) formation in breast cancer cells. PARPYnD is a robust tool for profiling PARP1/2 and is used to profile clinical PARP inhibitor olaparib, identifying several novel off-target proteins. Surprisingly, while PARPYnD can enrich recombinant PARP6 spiked into cellular lysates and inhibits PARP6 in cell-free assays, it does not label PARP6 in intact cells. These data highlight an intriguing biomolecular disparity between recombinant and endogenous PARP6. PARPYnD provides a new approach to expand our knowledge of the targets of this class of compounds and the mechanisms of action of PARP inhibitors in cancer.
AU  - Howard,RT
AU  - Hemsley,P
AU  - Petteruti,P
AU  - Saunders,CN
AU  - Molina,Bermejo JA
AU  - Scott,JS
AU  - Johannes,JW
AU  - Tate,EW
DO  - 10.1021/acschembio.9b00963
EP  - 333
PY  - 2020///
SN  - 1554-8929
SP  - 325
TI  - Structure-guided design and in-cell target profiling of a cell-active target engagement probe for PARP inhibitors
T2  - ACS Chemical Biology
UR  - http://dx.doi.org/10.1021/acschembio.9b00963
UR  - https://pubs.acs.org/doi/10.1021/acschembio.9b00963
UR  - http://hdl.handle.net/10044/1/77571
VL  - 15
ER  -
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Contact

Prof. Ed Tate
GSK Chair in Chemical Biology
Department of Chemistry
Molecular Sciences Research Hub, White City Campus,
82 Wood Lane, London, W12 0BZ

e.tate@imperial.ac.uk
Tel: +44 (0)20 759 + ext 43752 or 45821