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

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

  • Eur J Med Chem. 2020 Oct 15;204:112658. doi: 10.1016/j.ejmech.2020.112658.
Ahmed H Elmenoufy 1,  Francesco Gentile 2,  David Jay 3,  Feridoun Karimi-Busheri 3,  Xiaoyan Yang 3,  Olivier M Soueidan 4,  Rajam S Mani 3,  Gloria Ciniero 5,  Jack A Tuszynski 6,  Michael Weinfeld 3,  Frederick G West 7
Affiliations

Affiliations

  • 1 Department of Chemistry, University of Alberta, Edmonton, Alberta, T6G 2G2, Canada; Department of Pharmaceutical Chemistry, College of Pharmacy, Misr University for Science and Technology, 6th of October City, P.O. Box: 77, Egypt.
  • 2 Department of Physics, University of Alberta, Edmonton, Alberta, T6G 2E1, Canada.
  • 3 Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, Alberta, T6G 1Z2, Canada.
  • 4 Department of Chemistry, University of Alberta, Edmonton, Alberta, T6G 2G2, Canada.
  • 5 Department of Mechanical and Aerospace Engineering, Politecnico di Torino, Torino, 10129, Italy; Università di Torino, Torino, 10124, Italy.
  • 6 Department of Physics, University of Alberta, Edmonton, Alberta, T6G 2E1, Canada; Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, Alberta, T6G 1Z2, Canada.
  • 7 Department of Chemistry, University of Alberta, Edmonton, Alberta, T6G 2G2, Canada. Electronic address: [email protected].
PMID: 32738410 DOI: 10.1016/j.ejmech.2020.112658
Abstract

The structure-specific ERCC1-XPF endonuclease is essential for repairing bulky DNA lesions and helix distortions induced by UV radiation, which forms cyclobutane pyrimidine dimers (CPDs), or chemicals that crosslink DNA strands such as cyclophosphamide and platinum-based chemotherapeutic agents. Inhibition of the ERCC1-XPF endonuclease activity has been shown to sensitize Cancer cells to these chemotherapeutic agents. In this study, we have conducted a structure activity relationship analysis based around the previously identified hit compound, 4-((6-chloro-2-methoxyacridin-9-yl)amino)-2-((4-methylpiperazin1-yl)methyl)phenol (F06), as a reference compound. Three different series of compounds have been rationally designed and successfully synthesized through various modifications on three different sites of F06 based on the corresponding suggestions of the previous pharmacophore model. The in vitro screening results revealed that 2-chloro-9-((3-((4-(2-(dimethylamino)ethyl)piperazin-1-yl)methyl)-4-hydroxyphenyl)amino)acridin-2-ol (B9) has a potent inhibitory effect on the ERCC1-XPF activity (IC50 = 0.49 μM), showing 3-fold improvement in inhibition activity compared to F06. In addition, B9 not only displayed better binding affinity to the ERCC1-XPF complex but also had the capacity to potentiate the cytotoxicity effect of UV radiation and inhibiting the nucleotide excision repair, by the inhibition of removal of CPDs, and cyclophosphamide toxicity to colorectal Cancer cells.

Keywords

Colorectal cancer cells sensitisation; Cyclophosphamide potentiation; ERCC1-XPF small molecule inhibitors; Molecular docking; Targeted DNA repair therapy.

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