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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Clinical Validation Trial of ClarityDX Prostate, a made-in-Alberta blood test to improve the diagnosis of Prostate Cancer

John Lewis will be presenting a seminar entitled “Clinical Validation Trial of ClarityDX Prostate, a made-in-Alberta blood test to improve the diagnosis of Prostate Cancer” at the University of Alberta Urology Grand Rounds this Friday, Feb 8, at the NAUC Auditorium. Please come out and join us for this early morning seminar, your presence is appreciated!
John will discuss the progress in the discovery and clinical validation of novel biomarkers for prostate cancer detection and prognosis. He will also give an overview of the Alberta Prostate Cancer Registry and Biorepository recruitment and future plans, and an overview and goals of the upcoming ClarityDX Prostate blood test clinical validation trial.
Date: Friday, February 8, 2019
Time: 7:00 am – 8:00 am
Location: NAUC Auditorium (7th floor) in the Kaye Edmonton Clinic
See you on Friday!

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