Posted: June 30, 2014
Researchers at the University of Alberta have developed a family of small molecule inhibitors of the phosphatase function of human polynucleotide kinase/phosphatase (PNKP). Many aggressive cancers up-regulate DNA repair enzymes and become resistant to radiation or chemotherapy. DNA repair inhibitors can overcome resistance and ‘sensitize’ cancer cells, enhancing the efficacy of chemotherapeutic agents and radiation.
PNKP is an important enzyme in the DNA break repair pathway that processes and restores both double strand and single strand DNA breaks. Our novel PNKP inhibitors have been demonstrated to increase sensitivity of human lung and breast adenocarcinoma cell lines to topoisomerase I inhibitors and ionizing radiation.
PNKP inhibitors work alone to inhibit growth in cells deficient in tumor suppressor genes (eg. PTEN and SHP-1), and single stranded break repair proteins (including Poly ADP ribose polymerase (PARP) and DNA polymerase β) to induce synthetic lethality without the need for toxic radiation or chemotherapy.
In collaboration with the Centre for Drug Research and Development and the Alberta Cancer Foundation, research is currently underway to expand the compound family and explore preclinical development for colorectal and other cancers.
- target dsDNA and ssDNA break repair pathways.
- specifically inhibit PNKP phosphatase activity.
- have IC50 values comparable to PARP inhibitors and a good in vitro safety profile.
- are synthetically lethal with tumor suppressor and DNA repair defects
- demonstrate retention in solid target organs
US9,040,551 US9,115,406 US9,694,073 US10,087, 448
2008096, 2010061, 2016088
Technology Management Group
TEC Edmonton – University of Alberta