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Title: Diphenylpyrazoles as Replication Protein A inhibitors

Replication Protein A is the primary eukaryotic ssDNA binding protein that has a central role in initiating the cellular response to DNA damage. RPA recruits multiple proteins to sites of DNA damage via the N-terminal domain of the 70 kDa subunit (RPA70N). Here we describe the optimization of a diphenylpyrazole carboxylic acid series of inhibitors of these RPA–protein interactions. Lastly, we evaluated substituents on the aromatic rings as well as the type and geometry of the linkers used to combine fragments, ultimately leading to submicromolar inhibitors of RPA70N protein–protein interactions.
Authors:
 [1] ;  [1] ;  [1] ;  [1] ;  [1] ;  [1] ;  [1] ;  [1] ;  [1] ;  [1] ;  [1]
  1. Vanderbilt Univ., Nashville, TN (United States)
Publication Date:
Grant/Contract Number:
AC02-06CH11357
Type:
Accepted Manuscript
Journal Name:
ACS Medicinal Chemistry Letters
Additional Journal Information:
Journal Volume: 6; Journal Issue: 2; Journal ID: ISSN 1948-5875
Publisher:
American Chemical Society (ACS)
Research Org:
Vanderbilt Univ., Nashville, TN (United States)
Sponsoring Org:
USDOE Office of Science (SC)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; 37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; fragment-based discovery; medicinal chemistry; Replication protein A
OSTI Identifier:
1346168

Waterson, Alex G., Kennedy, J. Phillip, Patrone, James D., Pelz, Nicholas F., Feldkamp, Michael D., Frank, Andreas O., Vangamudi, Bhavatarini, Souza-Fagundes, Elaine M., Rossanese, Olivia W., Chazin, Walter J., and Fesik, Stephen W.. Diphenylpyrazoles as Replication Protein A inhibitors. United States: N. p., Web. doi:10.1021/ml5003629.
Waterson, Alex G., Kennedy, J. Phillip, Patrone, James D., Pelz, Nicholas F., Feldkamp, Michael D., Frank, Andreas O., Vangamudi, Bhavatarini, Souza-Fagundes, Elaine M., Rossanese, Olivia W., Chazin, Walter J., & Fesik, Stephen W.. Diphenylpyrazoles as Replication Protein A inhibitors. United States. doi:10.1021/ml5003629.
Waterson, Alex G., Kennedy, J. Phillip, Patrone, James D., Pelz, Nicholas F., Feldkamp, Michael D., Frank, Andreas O., Vangamudi, Bhavatarini, Souza-Fagundes, Elaine M., Rossanese, Olivia W., Chazin, Walter J., and Fesik, Stephen W.. 2014. "Diphenylpyrazoles as Replication Protein A inhibitors". United States. doi:10.1021/ml5003629. https://www.osti.gov/servlets/purl/1346168.
@article{osti_1346168,
title = {Diphenylpyrazoles as Replication Protein A inhibitors},
author = {Waterson, Alex G. and Kennedy, J. Phillip and Patrone, James D. and Pelz, Nicholas F. and Feldkamp, Michael D. and Frank, Andreas O. and Vangamudi, Bhavatarini and Souza-Fagundes, Elaine M. and Rossanese, Olivia W. and Chazin, Walter J. and Fesik, Stephen W.},
abstractNote = {Replication Protein A is the primary eukaryotic ssDNA binding protein that has a central role in initiating the cellular response to DNA damage. RPA recruits multiple proteins to sites of DNA damage via the N-terminal domain of the 70 kDa subunit (RPA70N). Here we describe the optimization of a diphenylpyrazole carboxylic acid series of inhibitors of these RPA–protein interactions. Lastly, we evaluated substituents on the aromatic rings as well as the type and geometry of the linkers used to combine fragments, ultimately leading to submicromolar inhibitors of RPA70N protein–protein interactions.},
doi = {10.1021/ml5003629},
journal = {ACS Medicinal Chemistry Letters},
number = 2,
volume = 6,
place = {United States},
year = {2014},
month = {11}
}