Publications

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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Kaye Fund Awards: Congratulations to our APCaRI members!

University Hospital Foundation – Kaye Fund Awards

Congratulations to two APCaRI principal investigators; Dr. John Lewis and Dr. Frank Wuest for their 2018 Kaye Fund Awards! From an initial field of 80 applicants, 7 Kaye Fund Awards in total were given to medical researchers studying a diverse array of health-relevant topics of huge importance to Albertans and the rest of the world alike.

John Lewis’ project is titled “Improving the Management of Prostate Cancer Using Advanced Biofluid Diagnostics” and Frank Wuest’s project is “Novel Radiolabeled PSMA Inhibitors for Clinical PET Imaging of Prostate Cancer”. Both projects are poised to greatly improve prostate cancer diagnosis and treatment in the near future.

The University of Alberta Hospital (UAH), Kaye Edmonton Clinic (KEC) and the University Hospital Foundation (UHF) launched the Kaye Fund Competition in the fall of 2017. Recipients of this inaugural competition were announced July 4th, 2018. The Kaye Fund Competition aims to support individuals or collaborative, inter-disciplinary and multi-disciplinary teams in the pursuit of research, innovation and quality improvement projects that will establish new approaches to patient care.

The Kaye Fund Award is funded by a transformational $30 million donation from Mr. Donald Kaye. This gift is directed to advancing patient care and medical research to the Kaye Edmonton Clinic, and remains one of largest donations in the history of Canadian healthcare philanthropy.

Mr. Donald Kaye

Through his naming gift to the University Hospital Foundation, Donald Kaye has transformed years of hard work, prudent decision-making and wise investing into one of the largest donations in the history of Canadian healthcare philanthropy. And in doing so, Mr. Kaye is advancing patient care and medical research in a way that is both intently focused, and broadly based.  

 

 

- Perrin Beatty