Open AccessDiphenylpyrazoles as Replication Protein A Inhibitors
Author(s) -
Alex G. Waterson,
J. Phillip Kennedy,
James D. Patrone,
Nicholas F. Pelz,
Michael D. Feldkamp,
Andreas O. Frank,
Bhavatarini Vangamudi,
Elaine M. Souza–Fagundes,
Olivia W. Rossanese,
Walter Chazin,
Stephen W. Fesik
Publication year - 2014
Publication title -
acs medicinal chemistry letters
Language(s) - Uncategorized
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/ml5003629
Subject(s) - protein subunit , dna replication , replication protein a , seqa protein domain , replication (statistics) , dna , chemistry , dna damage , microbiology and biotechnology , computational biology , biochemistry , dna binding protein , biophysics , eukaryotic dna replication , biology , gene , virology , transcription factor
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. 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.
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