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Publications

Small Molecule Inhibitors of ERCC1-XPF Protein-Protein Interaction Synergize Alkylating Agents in Cancer Cells

By:
Contributors: Jack Tuszynski Research Group
Mol Pharmacol. 2013 Jul;84(1):12-24. doi: 10.1124/mol.112.082347. Epub 2013 Apr 11.

Abstract

The benefit of cancer chemotherapy based on alkylating agents is limited because of the action of DNA repair enzymes, which mitigate the damage induced by these agents. The interaction between the proteins ERCC1 and XPF involves two major components of the nucleotide excision repair pathway. Here, novel inhibitors of this interaction were identified by virtual screening based on available structures with use of the National Cancer Institute diversity set and a panel of DrugBank small molecules. Subsequently, experimental validation of the in silico screening was undertaken. Top hits were evaluated on A549 and HCT116 cancer cells. In particular, the compound labeled NSC 130813 [4-[(6-chloro-2-methoxy-9-acridinyl)amino]-2-[(4-methyl-1-piperazinyl)methyl]] was shown to act synergistically with cisplatin and mitomycin C; to increase UVC-mediated cytotoxicity; to modify DNA repair as indicated by the staining of phosphorylated H2AX; and to disrupt interaction between ERCC1 and XPF in cells. In addition, using the Biacore technique, we showed that this compound interacts with the domain of XPF responsible for interaction with ERCC1. This study shows that small molecules targeting the protein-protein interaction of ERCC1 and XPF can be developed to enhance the effects of alkylating agents on cancer cells.

 

PubMed

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Its nearly time for the 2018 APCaRI Fall Symposium!

APCaRI will celebrate its 11th research meeting at the Banff Park Lodge, in Banff, Alberta on October 26 to 27, 2018. Please welcome our two invited speakers who will be joining the Symposium this year:

Alison Allan, PhD
Chair, Department of Anatomy & Cell Biology
Associate Professor, Departments of Anatomy & Cell Biology and Oncology
Western University, Ontario CA
and
Melina Cimler, PhD
CEO and Founder
PandiaDx LLC
Frisco, Texas

Previous fall symposia have had over 60 participants participating in this fun and enriching event, including clinicians, scientists, clinical research personnel, trainees, benefactors and representatives of PCa support groups.
Rose Pink Photography was at the 2017 APCaRI Fall Symposium and took these excellent images of the meeting, including the group photo seen in the featured image!

Plan on attending the 2018 Fall symposium to discuss and share ideas and enjoy the beautiful Rockies!
The APCaRI Fall symposium is generously supported by the Alberta Cancer Foundation and its’ donors.

- Perrin Beatty