Catechols and 3-hydroxypyridones as inhibitors of the DNA repair complex ERCC1-XPF

Chapman, Timothy M.; Gillen, Kevin J.; Wallace, Claire; Lee, Maximillian T.; Bakrania, Preeti; Khurana, Puneet; Coombs, P.J.; Stennett, Laura; Fox, Simon; Bureau, Emilie A.; Brownlees, Janet; Melton, David W.; Saxty, Barbara

doi:10.1016/j.bmcl.2015.08.031

Cited by 28 publications

(29 citation statements)

References 8 publications

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“…Arora et al reported that knocking down ERCC1-XPF resulted in reduced intrastrand repair and interstrand crosslinks repair, which makes about fourfold to sixfold changes in IC 50 value of cisplatin in NSCLC cells (Arora et al, 2010). Based on the above results, it is reasonable to believe that inhibiting ERCC1/XPF is a potential way to sensitize tumor cells to platinum-based chemotherapy, and many inhibitors are discovered: green tea polyphenol epigallocatechin-3-gallate, catechols, 3-hydroxypyridones, Nhydroxyimides, and hydroxypyrimidones (Chapman et al, 2015;Wang et al, 2015), but their clinical application still needs further investigation. Another nuclease function as ERCC1-XPF in NER is ERCC5 (XPG), which also relates to platinum sensitivity.…”

Section: Excision Repair Cross-complementingmentioning

confidence: 94%

The Drug-Resistance Mechanisms of Five Platinum-Based Antitumor Agents

et al. 2020

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Platinum-based anticancer drugs, including cisplatin, carboplatin, oxaliplatin, nedaplatin, and lobaplatin, are heavily applied in chemotherapy regimens. However, the intrinsic or acquired resistance severely limit the clinical application of platinum-based treatment. The underlying mechanisms are incredibly complicated. Multiple transporters participate in the active transport of platinum-based antitumor agents, and the altered expression level, localization, or activity may severely decrease the cellular platinum accumulation. Detoxification components, which are commonly increasing in resistant tumor cells, can efficiently bind to platinum agents and prevent the formation of platinum-DNA adducts, but the adducts production is the determinant step for the cytotoxicity of platinum-based antitumor agents. Even if adequate adducts have formed, tumor cells still manage to survive through increased DNA repair processes or elevated apoptosis threshold. In addition, autophagy has a profound influence on platinum resistance. This review summarizes the critical participators of platinum resistance mechanisms mentioned above and highlights the most potential therapeutic targets or predicted markers. With a deeper understanding of the underlying resistance mechanisms, new solutions would be produced to extend the clinical application of platinum-based antitumor agents largely.

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Section: Excision Repair Cross-complementingmentioning

confidence: 94%

The Drug-Resistance Mechanisms of Five Platinum-Based Antitumor Agents

et al. 2020

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“…More recently, several catechol and hydroxyl-imide/pyridine/pyrimidinones have been identified as ERCC1-XPF inhibitors from both in silico and high throughput screenings (Fig. 5) (Chapman et al, 2015; McNeil et al, 2015). Sub or low micromolar potency was observed in a biochemical endonuclease assay against XPF-ERCC1 with limited activity against FEN-1 and DNase I. E-X PPI2 significantly reduced the level of ERCC1-XPF heterodimers in ovarian cancer cells, inhibited NER with an IC 50 of 20 μM and enhances melanoma cell sensitivity to cisplatin.…”

Section: Ner Inhibitors and Combination Pt-therapymentioning

confidence: 99%

DNA repair targeted therapy: The past or future of cancer treatment?

Gavande

VanderVere-Carozza

Hinshaw

et al. 2016

Pharmacology & Therapeutics

332

282

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The repair of DNA damage is a complex process that relies on particular pathways to remedy specific types of damage to DNA. The range of insults to DNA includes small, modest changes in structure including mismatched bases and simple methylation events to oxidized bases, intra- and interstrand DNA crosslinks, DNA double strand breaks and protein-DNA adducts. Pathways required for the repair of these lesions include mismatch repair, base excision repair, nucleotide excision repair, and the homology directed repair/Fanconi anemia pathway. Each of these pathways contributes to genetic stability, and mutations in genes encoding proteins involved in these pathways have been demonstrated to promote genetic instability and cancer. In fact, it has been suggested all cancers display defects in DNA repair. It has also been demonstrated that the ability of cancer cells to repair therapeutically induced DNA damage impacts therapeutic efficacy. This has led to targeting DNA repair pathways and proteins to develop anti-cancer agents that will increase sensitivity to traditional chemotherapeutics. While initial studies languished and were plagued by a lack of specificity and a defined mechanism of action, more recent approaches to exploit synthetic lethal interaction and develop high affinity chemical inhibitors have proven considerably more effective. In this review we will highlight recent advances and discuss previous failures in targeting DNA repair to pave the way for future DNA repair targeted agents and their use in cancer therapy.

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“…More recently small molecules have been identified that target the protein-protein interaction domain of ERCC1-XPF and increase toxicity of alkylating agents in cancer cells. Another study has also identified assays and inhibitors of ERCC1-XPF using in silico approaches [17, 18] while studies utilizing biochemical approaches have identified small molecule inhibitors with micromolar potency [19, 20]. More recently, the first inhibitors of the ERCC1-XPF active site and interaction domain were identified that reduced the expression of the heterodimer as well as inhibited NER activity [21].…”

Section: Introductionmentioning

confidence: 99%

Identification of small molecule inhibitors of ERCC1-XPF that inhibit DNA repair and potentiate cisplatin efficacy in cancer cells

et al. 2016

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ERCC1-XPF heterodimer is a 5′-3′ structure-specific endonuclease which is essential in multiple DNA repair pathways in mammalian cells. ERCC1-XPF (ERCC1-ERCC4) repairs cisplatin-DNA intrastrand adducts and interstrand crosslinks and its specific inhibition has been shown to enhance cisplatin cytotoxicity in cancer cells. In this study, we describe a high throughput screen (HTS) used to identify small molecules that inhibit the endonuclease activity of ERCC1-XPF. Primary screens identified two compounds that inhibit ERCC1-XPF activity in the nanomolar range. These compounds were validated in secondary screens against two other non-related endonucleases to ensure specificity. Results from these screens were validated using an in vitro gel-based nuclease assay. Electrophoretic mobility shift assays (EMSAs) further show that these compounds do not inhibit the binding of purified ERCC1-XPF to DNA. Next, in lung cancer cells these compounds potentiated cisplatin cytotoxicity and inhibited DNA repair. Structure activity relationship (SAR) studies identified related compounds for one of the original Hits, which also potentiated cisplatin cytotoxicity in cancer cells. Excitingly, dosing with NSC16168 compound potentiated cisplatin antitumor activity in a lung cancer xenograft model. Further development of ERCC1-XPF DNA repair inhibitors is expected to sensitize cancer cells to DNA damage-based chemotherapy.

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Catechols and 3-hydroxypyridones as inhibitors of the DNA repair complex ERCC1-XPF

Cited by 28 publications

References 8 publications

The Drug-Resistance Mechanisms of Five Platinum-Based Antitumor Agents

The Drug-Resistance Mechanisms of Five Platinum-Based Antitumor Agents

DNA repair targeted therapy: The past or future of cancer treatment?

Identification of small molecule inhibitors of ERCC1-XPF that inhibit DNA repair and potentiate cisplatin efficacy in cancer cells

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