Design and Structure-Guided Development of Novel Inhibitors of the Xeroderma Pigmentosum Group A (XPA) Protein-DNA Interaction

Navnath S. Gavande, Pamela Vandervere-Carozza, Akaash K. Mishra, Tyler L. Vernon, Katherine S. Pawelczak, John Turchi

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

XPA is a unique and essential protein required for the nucleotide excision DNA repair pathway and represents a therapeutic target in oncology. Herein, we are the first to develop novel inhibitors of the XPA-DNA interaction through structure-guided drug design efforts. Ester derivatives of the compounds 1 (X80), 22, and 24 displayed excellent inhibitory activity (IC50 of 0.82 ± 0.18 μM and 1.3 ± 0.22 μM, respectively) but poor solubility. We have synthesized novel amide derivatives that retain potency and have much improved solubility. Furthermore, compound 1 analogs exhibited good specificity for XPA over RPA (replication protein A), another DNA-binding protein that participates in the nucleotide excision repair (NER) pathway. Importantly, there were no significant interactions observed by the X80 class of compounds directly with DNA. Molecular docking studies revealed a mechanistic model for the interaction, and these studies could serve as the basis for continued analysis of structure-activity relationships and drug development efforts of this novel target.

Original languageEnglish (US)
Pages (from-to)8055-8070
Number of pages16
JournalJournal of Medicinal Chemistry
Volume60
Issue number19
DOIs
StatePublished - Oct 12 2017

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ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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