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

Arora, Sanjeevani; Heyza, Joshua; Zhang, Hao; Kalman‐Maltese, Vivian; Tillison, Kristin; Floyd, Ashley M.; Chalfin, Elaine M.; Bepler, Gerold; Patrick, Steve M.

doi:10.18632/oncotarget.12072

Cited by 50 publications

(53 citation statements)

References 28 publications

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“…4d ). ERCC1 is an important gene regulating DNA repair 20 , which is a downstream gene of the AKT pathway 18 . Then, we found that PFKFB3 silencing reduced expression of AKT, pAKT, and ERCC1 (Fig.…”

Section: Resultsmentioning

confidence: 99%

PFKFB3 blockade inhibits hepatocellular carcinoma growth by impairing DNA repair through AKT

et al. 2018

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Overexpression of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), a key molecule of glucose metabolism in cytoplasm, has been found in various tumors. Emerging evidence has suggested that PFKFB3 is also located in the nucleus and apparent in regulatory functions other than glycolysis. In this study, we found that PFKFB3 expression is associated with hepatocellular carcinoma (HCC) growth and located mainly in the nucleus of tumor cells. PFKFB3 overexpression was associated with large tumor size (p = 0.04) and poor survival of patients with HCC (p = 0.027). Knockdown of PFKFB3 inhibited HCC growth, not only by reducing glucose consumption but also by damaging the DNA repair function, leading to G2/M phase arrest and apoptosis. In animal studies, overexpression of PFKFB3 is associated with increased tumor growth. Mechanistically, PFKFB3 silencing decreased AKT phosphorylation and reduced the expression of ERCC1, which is an important DNA repair protein. Moreover, PFK15, a selective PFKFB3 inhibitor, significantly inhibited tumor growth in a xenograft model of human HCC. PFKFB3 is a potential novel target in the treatment of HCC.

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Section: Resultsmentioning

confidence: 99%

PFKFB3 blockade inhibits hepatocellular carcinoma growth by impairing DNA repair through AKT

et al. 2018

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“…The investigation of post-translational modification and stability reported here led us to an alternative approach to target ERCC1-XPF. However, while this work was in progress, more encouraging results for conventional ERCC1-XPF inhibitors have been reported [ 43 , 44 ]. In particular, an ERCC1-XPF endonuclease inhibitor (IC50 < 1 μM), with specificity against another endonuclease and, despite only showing ˜2-fold enhanced sensitivity to cisplatin, potentiated cisplatin activity in a lung cancer xenograft model [ 44 ].…”

Section: Discussionmentioning

confidence: 99%

Disruption of DNA repair in cancer cells by ubiquitination of a destabilising dimerization domain of nucleotide excision repair protein ERCC1

2017

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DNA repair pathways present in all cells serve to preserve genome stability, but in cancer cells they also act reduce the efficacy of chemotherapy. The endonuclease ERCC1-XPF has an important role in the repair of DNA damage caused by a variety of chemotherapeutic agents and there has been intense interest in the use of ERCC1 as a predictive marker of therapeutic response in non-small cell lung carcinoma, squamous cell carcinoma and ovarian cancer. We have previously validated ERCC1 as a therapeutic target in melanoma, but all small molecule ERCC1-XPF inhibitors reported to date have lacked sufficient potency and specificity for clinical use. In an alternative approach to prevent the repair activity of ERCC1-XPF, we investigated the mechanism of ERCC1 ubiquitination and found that the key region was the C-terminal (HhH)2 domain which heterodimerizes with XPF. This ERCC1 region was modified by non-conventional lysine-independent, but proteasome-dependent polyubiquitination, involving Lys33 of ubiquitin and a linear ubiquitin chain. XPF was not polyubiquitinated and its expression was dependent on presence of ERCC1, but not vice versa. To our surprise we found that ERCC1 can also homodimerize through its C-terminal (HhH)2 domain. We exploited the ability of a peptide containing this C-terminal domain to destabilise both endogenous ERCC1 and XPF in human melanoma cells and fibroblasts, resulting in reductions of up to 85% in nucleotide excision repair and near two-fold increased sensitivity to DNA damaging agents. We suggest that the ERCC1 (HhH)2 domain could be used in an alternative strategy to treat cancer.

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“…The site is on the XPF nuclease domain and contains a number of charged residues and metal ions, which make it an attractive target for small molecule binding. Recently, several inhibitors have been reported, some of which have been shown to enhance chemotherapy in cell and xenograft tumor models (Arora et al, ; Chapman, Gillen, et al, ; Chapman, Wallace, et al, ; Gentile, Barakat, & Tuszynski, ; McNeil et al, ). However, the similarity between catalytic sites of several human divalent cation‐based DNA‐cleaving enzymes constitutes an obstacle to designing XPF‐specific inhibitors, and an experimental structure of the human XPF nuclease domain has not been solved yet (McNeil & Melton, ).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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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.

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

Cited by 50 publications

References 28 publications

PFKFB3 blockade inhibits hepatocellular carcinoma growth by impairing DNA repair through AKT

PFKFB3 blockade inhibits hepatocellular carcinoma growth by impairing DNA repair through AKT

Disruption of DNA repair in cancer cells by ubiquitination of a destabilising dimerization domain of nucleotide excision repair protein ERCC1

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

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