Selective inhibition of PARP10 using a chemical genetics strategy

Rory K. Morgan; Ian Carter-O'Connell; Michael S. Cohen

doi:10.1016/j.bmcl.2015.07.033

Selective inhibition of PARP10 using a chemical genetics strategy

Rory K. Morgan
, Ian Carter-O'Connell
, Michael S. Cohen

Chemical Physiology and Biochemistry

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

30 Scopus citations

Abstract

The lack of inhibitors that are selective for individual poly-ADP-ribose polymerase (PARP) family members has limited our understanding of their roles in cells. Here, we describe a chemical genetics approach for generating selective inhibitors of an engineered variant of PARP10. We synthesized a series of C-7 substituted 3,4-dihydroisoquinolin-1(2H)-one (dq) analogues designed to selectively inhibit a mutant of PARP10 (LG-PARP10) that contains a unique pocket in its active site. A dq analogue containing a bromo at the C-7 position demonstrated a 10-fold selectivity for LG-PARP10 compared to its WT counterpart. This study provides a platform for the development of selective inhibitors of individual PARP family members that will be useful for decoding their cellular functions.

Original language	English (US)
Pages (from-to)	4770-4773
Number of pages	4
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	25
Issue number	21
DOIs	https://doi.org/10.1016/j.bmcl.2015.07.033
State	Published - Nov 1 2015

Funding

We thank members of the Cohen laboratory for many helpful discussions. We thank P. Chang (MIT) for the GFP-PARP10 plasmid. This work was supported by an Achievement Rewards for College Scientists (ARCS) Scholarship and National Institutes of General Medicine Training Grant T32GM071338 (R.K.M) and National Institutes of Health Grant NS088629 (M.S.C.).

Funders	Funder number
National Institutes of General Medicine
Author National Institutes of Health National Institutes of Health National Institutes of Health National Institutes of Health The Bev Hartig Huntington's Disease Foundation National Institutes of Health	R01NS088629
National Institute of General Medical Sciences	T32GM071338

Keywords

ADP-ribosylation
Chemical genetics
Click chemistry
PARPs

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

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10.1016/j.bmcl.2015.07.033

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KW - Chemical genetics

KW - Click chemistry

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Selective inhibition of PARP10 using a chemical genetics strategy

Abstract

Funding

Keywords

ASJC Scopus subject areas

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