Release Date: 27-Feb-2023
The PARP protein participates in a number of cellular proteins including DNA repair, modification and transcription, among some others, and its inhibition was suggested as a promising treatment opportunity for several cancers. Many PARP inhibitors were developed but only some received approval and enjoyed market success. In all this, the therapeutic potential of another major protein that works alongside the PARP was largely ignored. The PARG protein reverses the action of the PARP enzyme and is also involved in DNA replication and repair. PARG has many other beneficial roles in plays within the cell and many recent research papers have demonstrated its potential as a therapeutic target. Though these revelations have not yet faired into the clinical trials satisfactorily, it is anticipated that novel PARG inhibitors for clinical use will be developed soon, especially now when there is dire requirement of drugs that can be used in patients suffering from any form of cancer.
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Many compounds targeting the PARG protein have been developed for research studies. PDD00017273 was the first-in-class PARG inhibitor was discovered at The University of Manchester’s Cancer Research Unit. Some other compounds include PDD00017272, NSC29192, NSC99657, NSC99667, NSC81474, COH34, RBPI-4 and GPI-16552. Nevertheless, their development never proceeded into preclinical studies. Studies with these PARG inhibitors have shown that the PARG proteins form a complex with BRCA1 in vivo, which essential for accurate DNA repair in the germline. BRCA1 is a protein known to be present in the tissues of the breast and plays a critical role in repairing damaged DNA, or destroying cells if DNA cannot be repaired. Therefore, inhibition of the PARG is an essential step to interfere with the repair of damaged DNA and causing cell death.
Further properties of PARG and the effects of its inhibition have not been studied extensively, mainly because of the lack of reliable animal models. However, inhibition of the PARG protein in mouse embryonic stem cells models in a research study showed that the depletion or silencing of PARG increases the sensitivity of cancer cells to ionizing radiation. Similarly, the process also increased the sensitivity of cells to different class of drugs that work by damaging the DNA. It has been suggested that this happens because of the reversal of the functions of the PARP proteins but there is no confirmation about the same because results from research studies understanding the effects of PARG depletion/deletion/inhibition on chemosensitizing have been variable.
IDE161, developed by Ideaya Biosciences is potentially a first-in-class small molecule inhibitor of PARG. The candidate is currently in the first phase of clinical trials in breast and ovarian cancers as a monotherapy. The candidate was identified through Ideaya’s internal drug-discovery platform. The drug candidate is anticipated to be substantially impactful for BRCA1 and BRCA2 patients who have been unresponsive to treatment with PARP inhibitors. As possibly the first candidate in clinical trials, IDE161 is expected to encourage the development of more PARG inhibitors though the promising results emerging from its ongoing clinical trial.
As a protein actively involved in DNA damage repair, the PARP protein has been studied extensively as a result of which, many PARP targeting drugs have entered the global pharmaceutical market. However, the PARG protein, which works along with the PARP has shown more therapeutic potential compared to the latter. Inhibition of the PARP protein by its inhibitors leads to its depletion, which as researchers have now shown, can be tolerated by cancer cells. In contrast, the inhibition, deletion or depletion of the PARG has shown to threaten cancer cell viability, which gives it an edge over PARP inhibitors. Pharmaceutical companies now need to address this key point while developing novel drugs. Though PARP inhibitors have a significant market share now, but it is expected to witness completion fromy PARG inhibitors for their advantages over them.