Structure-Guided Optimization of Replication Protein A (RPA)-DNA Interaction Inhibitors

Navnath S. Gavande, Navnath S. Gavande, Pamela S. Vandervere-Carozza, Katherine S. Pawelczak, Tyler L. Vernon, Matthew R. Jordan, John J. Turchi, John J. Turchi, John J. Turchi

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1118-1124
Number of pages7
JournalACS Medicinal Chemistry Letters
Volume11
Issue number6
DOIs
StatePublished - Jun 11 2020

Keywords

  • DNA damage and repair
  • Replication protein A
  • SAR
  • medicinal chemistry
  • reversible inhibitors

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry

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