Design, synthesis and in vitro cell-free/cell-based biological evaluations of novel ERCC1-XPF inhibitors targeting DNA repair pathway

Elmenoufy, Ahmed H.; Gentile, Francesco; Jay, David A.; Karimi‐Busheri, Feridoun; Yang, Xiaoyan; Soueidan, Olivier M; Mani, Rajam S.; Ciniero, Gloria; Tuszyński, Jack A.; Weinfeld, Michael; West, F. G.

doi:10.1016/j.ejmech.2020.112658

Cited by 7 publications

(6 citation statements)

References 32 publications

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“…The ADME results ( Table 2 ) when compared with the previous ADME screening of parent hit compound 1, and first and second generation compounds 4 ( 70 ) and 5 ( 71 ) indicated fairly similar responses to compound 4. However, two differences in the ADME data between compounds 6 and 4 may have a possible bearing on the lower sensitization capacity seen with compound 4 relative compound 6.…”

Section: Discussionmentioning

confidence: 70%

“…The most active compound (4, Figure 1 ) was then tested in HCT-116 cells and sensitized those cells to UVC radiation and cyclophosphamide treatment. Elmenoufy and co-workers ( 71 ) then investigated modifications of different sites on inhibitors 1 and 4. They found that inhibitor 5 ( Figure 1 ) with the methyl group masking the phenolic OH removed led to an increase in activity, and sensitized HCT-116 cells to UVC radiation and cyclophosphamide treatment.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2022

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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.

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Section: Discussionmentioning

confidence: 70%

Section: Introductionmentioning

confidence: 99%

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

et al. 2022

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“…As shown in Figure 3A, PYD markedly slowed the rate of release of the fluorescent oligonucleotide compared to the uninhibited control. Also included in Figure 3A are data previously obtained with three acridine-based inhibitors, i.e., B9, compound 4, and compound 1, indicating that inhibition by PYD compares favorably to inhibition by these compounds [29,30,55]. From the inset plot, an IC 50 of 0.321 ± 0.022 µM was calculated for PYD.…”

Section: Pyd Is An Inhibitor Of Ercc1-xpfmentioning

confidence: 90%

Repurposing Antimalarial Pyronaridine as a DNA Repair Inhibitor to Exploit the Full Potential of Gold-Nanoparticle-Mediated Radiation Response

et al. 2022

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Radiation therapy (RT) is frequently used to locally treat tumors. One of the major issues in RT is normal tissue toxicity; thus, it is necessary to limit dose escalation for enhanced local control in patients that have locally advanced tumors. Integrating radiosensitizing agents such as gold nanoparticles (GNPs) into RT has been shown to greatly increase the cure rate of solid tumors. The objective of this study was to explore the repurposing of an antimalarial drug, pyronaridine (PYD), as a DNA repair inhibitor to further enhance RT/GNP-induced DNA damage in cancerous cell lines. We were able to achieve inhibitory effects of DNA repair due to PYD at 500 nM concentration. Our results show a significant enhancement in DNA double-strand breaks of 42% in HeLa cells treated with PYD/GNP/RT in comparison to GNP/RT alone when irradiated with a dose of 2 Gy. Furthermore, there was a significant reduction in cellular proliferation for both HeLa and HCT-116 irradiated cells with the combined treatment of PYD/GNP/RT. Therefore, the emergence of promising novel concepts introduced in this study could lay the foundation for the transition of this treatment modality into clinical environments.

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“…The lead compounds B5/B9 and compound 4 showed 3-fold improvement in inhibition activity compared to F06. The sensitivity to UV radiation and cyclophosphamide also increased significantly in reducing proliferation of metastatic colorectal cancer ( 201 – 203 ). Moreover, compound 4 showed lower lipophilicity and greater metabolic stability which makes this compound an interesting candidate for further advancement.…”

Section: Inhibitors Targeting Ssa and Alt-nhej (Tmej) Pathwaysmentioning

confidence: 99%

Recent Advances in the Development of Non-PIKKs Targeting Small Molecule Inhibitors of DNA Double-Strand Break Repair

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The vast majority of cancer patients receive DNA-damaging drugs or ionizing radiation (IR) during their course of treatment, yet the efficacy of these therapies is tempered by DNA repair and DNA damage response (DDR) pathways. Aberrations in DNA repair and the DDR are observed in many cancer subtypes and can promote de novo carcinogenesis, genomic instability, and ensuing resistance to current cancer therapy. Additionally, stalled or collapsed DNA replication forks present a unique challenge to the double-strand DNA break (DSB) repair system. Of the various inducible DNA lesions, DSBs are the most lethal and thus desirable in the setting of cancer treatment. In mammalian cells, DSBs are typically repaired by the error prone non-homologous end joining pathway (NHEJ) or the high-fidelity homology directed repair (HDR) pathway. Targeting DSB repair pathways using small molecular inhibitors offers a promising mechanism to synergize DNA-damaging drugs and IR while selective inhibition of the NHEJ pathway can induce synthetic lethality in HDR-deficient cancer subtypes. Selective inhibitors of the NHEJ pathway and alternative DSB-repair pathways may also see future use in precision genome editing to direct repair of resulting DSBs created by the HDR pathway. In this review, we highlight the recent advances in the development of inhibitors of the non-phosphatidylinositol 3-kinase-related kinases (non-PIKKs) members of the NHEJ, HDR and minor backup SSA and alt-NHEJ DSB-repair pathways. The inhibitors described within this review target the non-PIKKs mediators of DSB repair including Ku70/80, Artemis, DNA Ligase IV, XRCC4, MRN complex, RPA, RAD51, RAD52, ERCC1-XPF, helicases, and DNA polymerase θ. While the DDR PIKKs remain intensely pursued as therapeutic targets, small molecule inhibition of non-PIKKs represents an emerging opportunity in drug discovery that offers considerable potential to impact cancer treatment.

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Design, synthesis and in vitro cell-free/cell-based biological evaluations of novel ERCC1-XPF inhibitors targeting DNA repair pathway

Cited by 7 publications

References 32 publications

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

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

Repurposing Antimalarial Pyronaridine as a DNA Repair Inhibitor to Exploit the Full Potential of Gold-Nanoparticle-Mediated Radiation Response

Recent Advances in the Development of Non-PIKKs Targeting Small Molecule Inhibitors of DNA Double-Strand Break Repair

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