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.
Keywords:
ADP-ribosylation; Chemical genetics; Click chemistry; PARPs.
Copyright © 2015 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Catalytic Domain / drug effects
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Dose-Response Relationship, Drug
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Genetic Engineering
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Humans
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Isoquinolines / chemical synthesis
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Isoquinolines / chemistry
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Isoquinolines / pharmacology*
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Molecular Structure
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Mutation
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Poly(ADP-ribose) Polymerase Inhibitors / chemical synthesis
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Poly(ADP-ribose) Polymerase Inhibitors / chemistry*
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Poly(ADP-ribose) Polymerase Inhibitors / pharmacology*
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Poly(ADP-ribose) Polymerases / chemistry
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Poly(ADP-ribose) Polymerases / genetics*
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Poly(ADP-ribose) Polymerases / metabolism
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Proto-Oncogene Proteins / antagonists & inhibitors*
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Proto-Oncogene Proteins / chemistry
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Proto-Oncogene Proteins / genetics*
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Proto-Oncogene Proteins / metabolism
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Structure-Activity Relationship
Substances
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3,4-dihydroisoquinolin-1(2H)-one
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Isoquinolines
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Poly(ADP-ribose) Polymerase Inhibitors
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Proto-Oncogene Proteins
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PARP10 protein, human
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Poly(ADP-ribose) Polymerases