Open AccessStructure-Guided Optimization of Replication Protein A (RPA)–DNA Interaction Inhibitors
Author(s) -
Navnath Gavande,
Pamela S. VanderVere-Carozza,
Katherine S. Pawelczak,
Tyler Ver,
Matthew R Jordan,
John J. Turchi
Publication year - 2020
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.9b00440
Subject(s) - replication protein a , dna , dna replication , computational biology , chemistry , drug discovery , dna damage , docking (animal) , dna repair , biochemistry , combinatorial chemistry , dna binding protein , biology , gene , medicine , transcription factor , nursing
Replication protein A (RPA) is the major human single stranded DNA (ssDNA)-binding protein, playing essential roles in DNA replication, repair, recombination, and DNA-damage response (DDR). Inhibition of RPA-DNA interactions represents a therapeutic strategy for cancer drug discovery and has great potential to provide single agent anticancer activity and to synergize with both common DNA damaging chemotherapeutics and newer targeted anticancer agents. In this letter, a new series of analogues based on our previously reported TDRL-551 ( 4 ) compound were designed to improve potency and physicochemical properties. Molecular docking studies guided molecular insights, and further SAR exploration led to the identification of a series of novel compounds with low micromolar RPA inhibitory activity, increased solubility, and excellent cellular up-take. Among a series of analogues, compounds 43, 44, 45 , and 46 hold promise for further development of novel anticancer agents.