Computer‐aided drug design of small molecule inhibitors of the ERCC1‐XPF protein–protein interaction

Abstract

The heterodimer of DNA excision repair protein ERCC‐1 and DNA repair endonuclease XPF (ERCC1‐XPF) is a 5′–3′ structure‐specific endonuclease essential for the nucleotide excision repair (NER) pathway, and it is also involved in other DNA repair pathways. In cancer cells, ERCC1‐XPF plays a central role in repairing DNA damage induced by chemotherapeutics including platinum‐based and cross‐linking agents; thus, its inhibition is a promising strategy to enhance the effect of these therapies. In this study, we rationally modified the structure of F06, a small molecule inhibitor of the ERCC1‐XPF interaction (Molecular Pharmacology, 84, 2013 and 12), to improve its binding to the target. We followed a multi‐step computational approach to investigate potential modification sites of F06, rationally design and rank a library of analogues, and identify candidates for chemical synthesis and in vitro testing. Our top compound, B5, showed an improved half‐maximum inhibitory concentration (IC50) value of 0.49 µM for the inhibition of ERCC1‐XPF endonuclease activit, and lays the foundation for further testing and optimization. Also, the computational approach reported here can be used to develop DNA repair inhibitors targeting the ERCC1‐XPF complex.

Targeting protein–protein interactions in the DNA damage response pathways for cancer chemotherapy

“…259 A second round of F06 optimization of culminated in the design of B5, which inhibited nuclease activity of the XPF-ERCC1 complex with an IC 50 of 0.49 μM (Figure 7). 258 Taken together, these studies indicate that further optimization of the F06 scaffold is a promising avenue to develop effective chemotherapeutic sensitizers that inhibit XPF-ERCC1 PPI in NER.…”

“…7 ). 258 Taken together, these studies indicate that further optimization of the F06 scaffold is a promising avenue to develop effective chemotherapeutic sensitizers that inhibit XPF-ERCC1 PPI in NER.…”

“…255 XPF-ERCC1 is a major chemotherapeutic target with a few inhibitors identified. [256][257][258][259][260] XPF and ERCC1 form a heterodimer via mainly hydrophobic interactions between their double helix-hairpin-helix (HhH 2 ) C-terminal regions (PDB: 2A1J, 1Z00, 6SXA, 6SXB). [261][262][263] Researchers at the University of Edinburgh utilized in silico SBVS to target pockets on the XPF binding site for ERCC1, resulting in identification of 29 compound hits, 4 of which were confirmed to bind XPF by SPR.…”

“…In the follow-up study, optimization of F06 was carried out via docking, pharmacophore modeling, and MD, resulting in seven F06 derivatives. 258 One of the analogues, F06-4 (Figure 7), sensitized colon cancer cells to UV radiation and cyclophosphamide, exhibited IC 50 of 0.33 μM (improved 5-fold over 1.86 μM for F06), and displayed favorable physicochemical and ligand efficiency profiles, suggesting it may be effective in vivo. 259 A second round of F06 optimization of culminated in the design of B5, which inhibited nuclease activity of the XPF-ERCC1 complex with an IC 50 of 0.49 μM (Figure 7).…”

Targeting cancer drug resistance by modulation of ERCC1-XPF and p53 activity

“…The ERCC1-XPF 5'-3' DNA endonuclease complex is involved in the nucleotide excision repair (NER) pathway, which is one of the key mechanisms responsible for resistance development to chemotherapeutic agents. [1][2][3][4] A strategy to improve effects of traditional crosslinking drugs and reduce development of resistance is to target both the endonuclease and p53. These proteins play a key role in the efficacy of DNA damage induced apoptosis.…”