Enhancing the activity of platinum-based drugs by improved inhibitors of ERCC1–XPF-mediated DNA repair

Ciniero, Gloria; Elmenoufy, Ahmed H.; Gentile, Francesco; Weinfeld, Michael; Deriu, Marco Agostino; West, F. G.; Tuszyński, Jack A.; Dumontet, Charles; Cros‐Perrial, Emeline; Jordheim, Lars Petter

doi:10.1007/s00280-020-04213-x

Cited by 9 publications

(12 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, when media containing 2 μM concentration of compound 6 is added the number of foci per cell drops to an average of 3 per cell, showing a clear disruption of ERCC1-XPF heterodimerization ( Figure 5 ). This result is in keeping with the PLA results previously observed for 1, 4, and 5 ( 73 ), where this series of inhibitors showed clear inhibition of the interaction between ERCC1 and XPF when A549 cells were treated with 20 μM cisplatin and 1 μM concentrations of the inhibitors. However, only compound 5 showed any significant disruption of ERCC1-XPF heterodimerization on A549 not treated with cisplatin in those experiments.…”

Section: Discussionsupporting

confidence: 92%

“…A previously published protocol ( 73 ) was followed with minor modifications. Briefly, 3 x 10 4 A549 cells were seeded in each well of an 8-well Chamber Slide system (Ibidi.…”

Section: Methodsmentioning

confidence: 99%

“…Importantly, Ciniero et al. ( 73 ) were able to show that 5 sensitized HCT-116 and A549 cells to cisplatin and mitomycin C, they were also able to show, via a proximity ligation assay, that sensitization of A549 cells to cisplatin was due to inhibition of the heterodimerization of ERCC1-XPF.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Modulation of ERCC1-XPF Heterodimerization Inhibition via Structural Modification of Small Molecule Inhibitor Side-Chains

et al. 2022

Self Cite

View full text Add to dashboard Cite

Inhibition of DNA repair enzymes is an attractive target for increasing the efficacy of DNA damaging chemotherapies. The ERCC1-XPF heterodimer is a key endonuclease in numerous single and double strand break repair processes, and inhibition of the heterodimerization has previously been shown to sensitize cancer cells to DNA damage. In this work, the previously reported ERCC1-XPF inhibitor 4 was used as the starting point for an in silico study of further modifications of the piperazine side-chain. A selection of the best scoring hits from the in silico screen were synthesized using a late stage functionalization strategy which should allow for further iterations of this class of inhibitors to be readily synthesized. Of the synthesized compounds, compound 6 performed the best in the in vitro fluorescence based endonuclease assay. The success of compound 6 in inhibiting ERCC1-XPF endonuclease activity in vitro translated well to cell-based assays investigating the inhibition of nucleotide excision repair and disruption of heterodimerization. Subsequently compound 6 was shown to sensitize HCT-116 cancer cells to treatment with UVC, cyclophosphamide, and ionizing radiation. This work serves as an important step towards the synergistic use of DNA repair inhibitors with chemotherapeutic drugs.

show abstract

Section: Discussionsupporting

confidence: 92%

“…A previously published protocol ( 73 ) was followed with minor modifications. Briefly, 3 x 10 4 A549 cells were seeded in each well of an 8-well Chamber Slide system (Ibidi.…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Modulation of ERCC1-XPF Heterodimerization Inhibition via Structural Modification of Small Molecule Inhibitor Side-Chains

et al. 2022

Self Cite

View full text Add to dashboard Cite

show abstract

“…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.…”

Section: Introductionmentioning

confidence: 99%

“…Indeed, a loss of function in p53 allows cells to survive despite great genomic impairment. 3 The overall objectives of the present study are: i) to shed light on the above-mentioned mechanisms, ii) to evaluate, by in vitro tests, the efficacy of in silico predicted ERCC1-XPF inhibitors 1,4 on both p53 WT and p53 negative cells.…”

Section: Introductionmentioning

confidence: 99%