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

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.