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Design, synthesis and evaluation of potent and selective inhibitors of mono-(ADP-ribosyl)transferases PARP10 and PARP14

Holechek, Jacob ; Lease, Robert ; Thorsell, Ann-Gerd ; Karlberg, Tobias LU ; McCadden, Caitlin ; Grant, Ryan ; Keen, Abby ; Callahan, Evan ; Schüler, Herwig LU orcid and Ferraris, Dana (2018) In Bioorganic & Medicinal Chemistry Letters 28(11). p.2050-2054
Abstract

A series of diaryl ethers were designed and synthesized to discern the structure activity relationships against the two closely related mono-(ADP-ribosyl)transferases PARP10 and PARP14. Structure activity studies identified 8b as a sub-micromolar inhibitor of PARP10 with ∼15-fold selectivity over PARP14. In addition, 8k and 8m were discovered to have sub-micromolar potency against PARP14 and demonstrated moderate selectivity over PARP10. A crystal structure of the complex of PARP14 and 8b shows binding of the compound in a novel hydrophobic pocket and explains both potency and selectivity over other PARP family members. In addition, 8b, 8k and 8m also demonstrate selectivity over PARP1. Together, this study identified novel, potent and... (More)

A series of diaryl ethers were designed and synthesized to discern the structure activity relationships against the two closely related mono-(ADP-ribosyl)transferases PARP10 and PARP14. Structure activity studies identified 8b as a sub-micromolar inhibitor of PARP10 with ∼15-fold selectivity over PARP14. In addition, 8k and 8m were discovered to have sub-micromolar potency against PARP14 and demonstrated moderate selectivity over PARP10. A crystal structure of the complex of PARP14 and 8b shows binding of the compound in a novel hydrophobic pocket and explains both potency and selectivity over other PARP family members. In addition, 8b, 8k and 8m also demonstrate selectivity over PARP1. Together, this study identified novel, potent and metabolically stable derivatives to use as chemical probes for these biologically interesting therapeutic targets.

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author
; ; ; ; ; ; ; ; and
publishing date
type
Contribution to journal
publication status
published
keywords
Amides/chemical synthesis, Dose-Response Relationship, Drug, Drug Design, Ethers/chemical synthesis, Humans, Molecular Structure, Poly(ADP-ribose) Polymerase Inhibitors/chemical synthesis, Poly(ADP-ribose) Polymerases/metabolism, Proto-Oncogene Proteins/antagonists & inhibitors, Structure-Activity Relationship
in
Bioorganic & Medicinal Chemistry Letters
volume
28
issue
11
pages
5 pages
publisher
Elsevier
external identifiers
  • scopus:85046630912
  • pmid:29748053
ISSN
0960-894X
DOI
10.1016/j.bmcl.2018.04.056
language
English
LU publication?
no
additional info
Copyright © 2018 Elsevier Ltd. All rights reserved.
id
5997115b-a3c3-4fde-803f-2fa11f75306a
date added to LUP
2024-11-21 17:49:45
date last changed
2025-04-11 21:49:20
@article{5997115b-a3c3-4fde-803f-2fa11f75306a,
  abstract     = {{<p>A series of diaryl ethers were designed and synthesized to discern the structure activity relationships against the two closely related mono-(ADP-ribosyl)transferases PARP10 and PARP14. Structure activity studies identified 8b as a sub-micromolar inhibitor of PARP10 with ∼15-fold selectivity over PARP14. In addition, 8k and 8m were discovered to have sub-micromolar potency against PARP14 and demonstrated moderate selectivity over PARP10. A crystal structure of the complex of PARP14 and 8b shows binding of the compound in a novel hydrophobic pocket and explains both potency and selectivity over other PARP family members. In addition, 8b, 8k and 8m also demonstrate selectivity over PARP1. Together, this study identified novel, potent and metabolically stable derivatives to use as chemical probes for these biologically interesting therapeutic targets.</p>}},
  author       = {{Holechek, Jacob and Lease, Robert and Thorsell, Ann-Gerd and Karlberg, Tobias and McCadden, Caitlin and Grant, Ryan and Keen, Abby and Callahan, Evan and Schüler, Herwig and Ferraris, Dana}},
  issn         = {{0960-894X}},
  keywords     = {{Amides/chemical synthesis; Dose-Response Relationship, Drug; Drug Design; Ethers/chemical synthesis; Humans; Molecular Structure; Poly(ADP-ribose) Polymerase Inhibitors/chemical synthesis; Poly(ADP-ribose) Polymerases/metabolism; Proto-Oncogene Proteins/antagonists & inhibitors; Structure-Activity Relationship}},
  language     = {{eng}},
  month        = {{06}},
  number       = {{11}},
  pages        = {{2050--2054}},
  publisher    = {{Elsevier}},
  series       = {{Bioorganic & Medicinal Chemistry Letters}},
  title        = {{Design, synthesis and evaluation of potent and selective inhibitors of mono-(ADP-ribosyl)transferases PARP10 and PARP14}},
  url          = {{http://dx.doi.org/10.1016/j.bmcl.2018.04.056}},
  doi          = {{10.1016/j.bmcl.2018.04.056}},
  volume       = {{28}},
  year         = {{2018}},
}