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

• Published in: Journal of medicinal chemistry Vol. 60; no. 19; pp. 8055 - 8070
• Main Authors: Gavande, Navnath S, VanderVere-Carozza, Pamela, Mishra, Akaash K, Vernon, Tyler L, Pawelczak, Katherine S, Turchi, John J
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 12-10-2017
• Subjects: Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Computer Simulation; DNA - drug effects; DNA Repair - drug effects; Drug Design; Drug Evaluation, Preclinical; Humans; Intercalating Agents - chemical synthesis; Intercalating Agents - chemistry; Intercalating Agents - pharmacology; Models, Molecular; Molecular Docking Simulation; Solubility; Structure-Activity Relationship; Xeroderma Pigmentosum Group A Protein - antagonists & inhibitors
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.7b00780

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.