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Small Molecule Microarray Based Discovery of PARP14 Inhibitors

Peng, Bo ; Thorsell, Ann-Gerd ; Karlberg, Tobias LU ; Schüler, Herwig LU orcid and Yao, Shao Q (2017) In Angewandte Chemie (International edition) 56(1). p.248-253
Abstract

Poly(ADP-ribose) polymerases (PARPs) are key enzymes in a variety of cellular processes. Most small-molecule PARP inhibitors developed to date have been against PARP1, and suffer from poor selectivity. PARP14 has recently emerged as a potential therapeutic target, but its inhibitor development has trailed behind. Herein, we describe a small molecule microarray-based strategy for high-throughput synthesis, screening of >1000 potential bidentate inhibitors of PARPs, and the successful discovery of a potent PARP14 inhibitor H10 with >20-fold selectivity over PARP1. Co-crystallization of the PARP14/H10 complex indicated H10 bound to both the nicotinamide and the adenine subsites. Further structure-activity relationship studies... (More)

Poly(ADP-ribose) polymerases (PARPs) are key enzymes in a variety of cellular processes. Most small-molecule PARP inhibitors developed to date have been against PARP1, and suffer from poor selectivity. PARP14 has recently emerged as a potential therapeutic target, but its inhibitor development has trailed behind. Herein, we describe a small molecule microarray-based strategy for high-throughput synthesis, screening of >1000 potential bidentate inhibitors of PARPs, and the successful discovery of a potent PARP14 inhibitor H10 with >20-fold selectivity over PARP1. Co-crystallization of the PARP14/H10 complex indicated H10 bound to both the nicotinamide and the adenine subsites. Further structure-activity relationship studies identified important binding elements in the adenine subsite. In tumor cells, H10 was able to chemically knockdown endogenous PARP14 activities.

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author
; ; ; and
publishing date
type
Contribution to journal
publication status
published
keywords
Drug Discovery, High-Throughput Screening Assays, Humans, Microarray Analysis, Poly(ADP-ribose) Polymerase Inhibitors/chemical synthesis, Poly(ADP-ribose) Polymerases/metabolism, Small Molecule Libraries/chemical synthesis, Structure-Activity Relationship
in
Angewandte Chemie (International edition)
volume
56
issue
1
pages
6 pages
publisher
John Wiley & Sons Inc.
external identifiers
  • scopus:85006494474
  • pmid:27918638
ISSN
1521-3773
DOI
10.1002/anie.201609655
language
English
LU publication?
no
additional info
© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.
id
55de8176-b153-41df-9153-f0a48c351a67
date added to LUP
2024-11-21 17:51:47
date last changed
2025-07-04 23:28:14
@article{55de8176-b153-41df-9153-f0a48c351a67,
  abstract     = {{<p>Poly(ADP-ribose) polymerases (PARPs) are key enzymes in a variety of cellular processes. Most small-molecule PARP inhibitors developed to date have been against PARP1, and suffer from poor selectivity. PARP14 has recently emerged as a potential therapeutic target, but its inhibitor development has trailed behind. Herein, we describe a small molecule microarray-based strategy for high-throughput synthesis, screening of &gt;1000 potential bidentate inhibitors of PARPs, and the successful discovery of a potent PARP14 inhibitor H10 with &gt;20-fold selectivity over PARP1. Co-crystallization of the PARP14/H10 complex indicated H10 bound to both the nicotinamide and the adenine subsites. Further structure-activity relationship studies identified important binding elements in the adenine subsite. In tumor cells, H10 was able to chemically knockdown endogenous PARP14 activities.</p>}},
  author       = {{Peng, Bo and Thorsell, Ann-Gerd and Karlberg, Tobias and Schüler, Herwig and Yao, Shao Q}},
  issn         = {{1521-3773}},
  keywords     = {{Drug Discovery; High-Throughput Screening Assays; Humans; Microarray Analysis; Poly(ADP-ribose) Polymerase Inhibitors/chemical synthesis; Poly(ADP-ribose) Polymerases/metabolism; Small Molecule Libraries/chemical synthesis; Structure-Activity Relationship}},
  language     = {{eng}},
  month        = {{01}},
  number       = {{1}},
  pages        = {{248--253}},
  publisher    = {{John Wiley & Sons Inc.}},
  series       = {{Angewandte Chemie (International edition)}},
  title        = {{Small Molecule Microarray Based Discovery of PARP14 Inhibitors}},
  url          = {{http://dx.doi.org/10.1002/anie.201609655}},
  doi          = {{10.1002/anie.201609655}},
  volume       = {{56}},
  year         = {{2017}},
}