Inhibiting the PARG enzyme could be a good way to fight ovarian cancer, according to a study.
The research, “First-In-Class Chemical Probes Against Poly(ADP-Ribose) Glycohydrolase (PARG) Inhibit DNA Repair With Differential Pharmacology To Olaparib,” was published in the journal ACS Chemical Biology.
Cancer cells are constantly multiplying, but the division process can include errors that cause the cells’ death, such as DNA breaks. Therapies that block DNA repair enzymes, or PARP inhibitors — such as Lynparza — have shown promise in treating ovarian cancer.
Both PARG and PARPs are involved in DNA repair.
PARP inhibitors can lead to an accumulation of DNA errors in cells with a defective DNA repair system, eventually translating into the cells’ death.
Not all patients respond to PARP-inhibiting therapy, however. The reason is there are a lot of PARP family members, and drugs target only two or three.
PARG plays a crucial role in repairing DNA breaks. This means that inhibiting the enzyme could be a valuable strategy for fighting cancer.
The exact mechanism by which PARG works is not understood, however, largely due to a lack of reliable chemical probes that allow researchers to manipulate its activity.
“The advantage of going after PARG is that there is only one member of its family,” Allan Jordan, one of the study’s authors, said in a news release. “So when you inhibit PARG, you may create a more effective roadblock in DNA repair.”
Both PARG and PARPs are part of the same DNA repair mechanism, and need one another to complete the process. Blocking PARG prevents PARP from working properly, contributing to cancer cell death.
Researchers discussed with the pharmaceutical company AstraZeneca their hypothesis that inhibiting PARG could be a way to fight cancer. The company told them it had already started looking among 1.4 million potential therapies for any that could prevent PARG activity.
“The number of molecules that AstraZeneca had already looked at told us we were facing quite a challenge,” Jordan said. “But it was a challenge we were willing to take on.”
Looking through all of the experimental drugs that AstraZeneca had available, researchers identified one that was a particularly promising way to block PARG activity. Indeed, the therapy was even better at killing cancer cells in culture than PARP inhibitors.
“This is not going to lead to a new treatment for patients overnight,” Jordan said. “First we need to understand the biology, how the experimental drug works and how to find which patients it works best for, before we can get it into clinical trials and patients.”
The new tool may increase scientists’ understanding of DNA repair, leading to the development of novel therapies against cancer, the researchers said.
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