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Small molecule inhibitors of PNKP, a DNA repair enzyme, for cancer therapy

Summary

TEC Edmonton is seeking collaborative development and licensing partners for novel radio/chemosensitizing agents. Researchers at the University of Alberta have identified potent small molecule inhibitors of a new DNA repair target, human polynucleotide kinase/phosphatase (PNKP). PNKP is an important enzyme in the DNA break repair pathway that processes and restores both double strand and single strand DNA breaks. Many aggressive cancers up-regulate DNA repair enzymes and become resistant to radiation or chemotherapy. Inhibitors of DNA repair pathways can overcome this resistance and thereby ‘sensitize’ cancer cells and enhance the efficacy of chemotherapeutic agents.

The PNKP inhibitors have been demonstrated to increase sensitivity of human lung and breast adenocarcinoma cell lines to topoisomerase I inhibitors and ionizing radiation. Furthermore, PNKP inhibitors work synergistically in cells deficient (inherent or siRNA induced) in other tumor suppressor genes (eg. ING2, CDKN3, and PTPN6), 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.

Medicinal chemistry efforts to optimize efficacy and preclinical testing are underway in collaboration with the Center for Drug Research and Development.

Supplementary Information

Patent Number: EP2440203A1
Application Number: EP2010782872A
Inventor: WEINFELD, Michael | HALL, Dennis, G. | KARIMI-BUSHERI, Feridoun | FRESCHAUF, Gary, Kenneth | MERENIUK, Todd, Randall
Priority Date: 4 Jun 2009
Priority Number: EP2440203A1
Application Date: 4 Jun 2010
Publication Date: 18 Apr 2012
IPC Current: A61K0031437 | A61K00314745 | A61N000500 | A61P003500 | C07D047104 | C12N000914 | C12N000999
Assignee Applicant: The Governors of the University of Alberta,Edmonton, Alberta T5J 4P6,101105761 | Alberta Health Services,Edmonton AB T5J 3N4,101164259
Title: SMALL MOLECULE INHIBITORS OF POLYNUCLEOTIDE KINASE/PHOSPHATASE. POLY(ADP-RIBOSE) POLYMERASE AND USES THEREOF | KLEINMOLEKÜL-HEMMER DER POLYNUKLEOTIDKINASE BZW. PHOSPHATASE POLY(ADP-RIBOSE)-POLYMERASE UND VERWENDUNGEN DAVON | INHIBITEURS À PETITE MOLÉCULE
Usefulness: SMALL MOLECULE INHIBITORS OF POLYNUCLEOTIDE KINASE/PHOSPHATASE. POLY(ADP-RIBOSE) POLYMERASE AND USES THEREOF | KLEINMOLEKÜL-HEMMER DER POLYNUKLEOTIDKINASE BZW. PHOSPHATASE POLY(ADP-RIBOSE)-POLYMERASE UND VERWENDUNGEN DAVON | INHIBITEURS À PETITE MOLÉCULE DE POLYNUCLÉOTIDE KINASE/PHOSPHATASE POLY(ADP-RIBOSE) POLYMÉRASE ET UTILISATIONS DE CEUX-CI
Summary: For increasing the sensitivity of a cancerous cell of a patient to a chemotherapeutic agent or radiation therapy for treating a cancer of the bladder, brain, breast, cervix, larynx, lung, prostate, vagina, thyroid, pancreas, ovary, breast, uterus, gallbladder, perianal and pelvic regions; colorectal cancer; gynecological cancer; cancer of the small intestine; small cell lung cancer; head and neck cancer; bronchial cancer; oral cancer; rectal cancer; tracheal cancer; or adult non-Hodgkin lymphoma; metastatic carcinoma of the colon or rectum; small cell lung cancer sensitive disease stage IV-B recurrent; persistent carcinoma of the cervix; relapsed small cell lung cancer; gastric cancer, or esophageal cancer in a human, non-human mammal, a rodent, a companion animal or livestock; or for treating a disorder associated with a defect in DNA polymeraseβ , where the disorder is a cancer (all claimed).
Novelty: Use of pyrrolopyridine compounds, e.g. 2-(1-hydroxyundecyl)-1-(4-nitrophenylamino)-6-phenyl-dihydro-1H-pyrrolo(3,4-b)pyridine-5,7(2H,4aH)-dione, for increasing sensitivity of a cancerous cell to a chemotherapeutic agent or radiation therapy

Industry

Disease Diagnostic/Treatment

Sub Category

Cancer/Tumor

Application No.

US serial no. 13/375,876
Canadian serial no. 2,764,234
European serial no. 10782872.5

ID No.

2008096

Country/Region

Canada