Diphenylpyrazoles as replication protein a inhibitors.
AUTHORS
Waterson
AGAlex G ,
Kennedy
JPJ Phillip ,
Patrone
JDJames D ,
Pelz
NFNicholas F ,
Feldkamp
MDMichael D ,
Frank
AOAndreas O ,
Vangamudi
BBhavatarini ,
Souza-Fagundes
EMElaine M ,
Rossanese
OWOlivia W ,
Chazin
WJWalter J ,
Fesik
SWStephen W .
ACS medicinal chemistry letters. 2015 2 12; 6(2).
140-5
- PMID: 25699140[PubMed].
- PMCID: PMC4329576.
ABSTRACT
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.