Structure-guided design and in-cell target profiling of a cell-active target engagement probe for PARP inhibitors
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
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.
Date Issued
2020-02-04
Date Acceptance
2020-02-04
Citation
ACS Chemical Biology, 2020, 15 (2), pp.325-333
ISSN
1554-8929
Publisher
American Chemical Society (ACS)
Start Page
325
End Page
333
Journal / Book Title
ACS Chemical Biology
Volume
15
Issue
2
Copyright Statement
© 2020 American Chemical Society. This is an open access article published under a Creative Commons Attribution (CC-BY) (http://pubs.acs.org/page/policy/authorchoice_ccby_termsofuse.html)
License, which permits unrestricted use, distribution and reproduction in any medium,
provided the author and source are cited.
License, which permits unrestricted use, distribution and reproduction in any medium,
provided the author and source are cited.
Identifier
https://pubs.acs.org/doi/10.1021/acschembio.9b00963
Subjects
Organic Chemistry
03 Chemical Sciences
06 Biological Sciences
Publication Status
Published online
Article Number
acschembio.9b00963
Date Publish Online
2020-02-04