1945950-21-9

Usage

Uses

Used in Pharmaceutical Research:
PDD00017273 is used as a chemical probe for [application reason] in the pharmaceutical industry. Its ability to inhibit DNA repair through targeting PARG makes it a promising candidate for the development of novel therapeutic strategies against diseases with aberrant DNA repair mechanisms.
Used in DNA Repair Inhibition:
PDD00017273 is used as a DNA repair inhibitor for studying the role of PARG in DNA repair processes. By inhibiting PARG, PDD00017273 can help researchers understand the underlying mechanisms of DNA repair and potentially develop targeted therapies for conditions where DNA repair is a critical factor.
Used in Cancer Research:
In the field of cancer research, PDD00017273 is used as a chemical probe to investigate the potential of PARG inhibition in cancer treatment. Its differential pharmacological properties compared to olaparib may offer new insights into the development of more effective cancer therapies, particularly for tumors with specific DNA repair deficiencies.

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Relevant academic research and scientific papers

First-in-class chemical probes against poly(ADP-ribose) glycohydrolase (PARG) inhibit DNA repair with differential pharmacology to olaparib

The enzyme poly(ADP-ribose) glycohydrolase (PARG) performs a critical role in the repair of DNA single strand breaks (SSBs). However, a detailed understanding of its mechanism of action has been hampered by a lack of credible, cell-active chemical probes. Herein, we demonstrate inhibition of PARG with a small molecule, leading to poly(ADP-ribose) (PAR) chain persistence in intact cells. Moreover, we describe two advanced, and chemically distinct, cell-active tool compounds with convincing on-target pharmacology and selectivity. Using one of these tool compounds, we demonstrate pharmacology consistent with PARG inhibition. Further, while the roles of PARG and poly(ADP-ribose) polymerase (PARP) are closely intertwined, we demonstrate that the pharmacology of a PARG inhibitor differs from that observed with the more thoroughly studied PARP inhibitor olaparib. We believe that these tools will facilitate a wider understanding of this important component of DNA repair and may enable the development of novel therapeutic agents exploiting the critical dependence of tumors on the DNA damage response (DDR).

Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides

DNA damage repair enzymes are promising targets in the development of new therapeutic agents for a wide range of cancers and potentially other diseases. The enzyme poly(ADP-ribose) glycohydrolase (PARG) plays a pivotal role in the regulation of DNA repair mechanisms; however, the lack of potent drug-like inhibitors for use in cellular and in vivo models has limited the investigation of its potential as a novel therapeutic target. Using the crystal structure of human PARG in complex with the weakly active and cytotoxic anthraquinone 8a, novel quinazolinedione sulfonamides PARG inhibitors have been identified by means of structure-based virtual screening and library design. 1-Oxetan-3-ylmethyl derivatives 33d and 35d were selected for preliminary investigations in vivo. X-ray crystal structures help rationalize the observed structure-activity relationships of these novel inhibitors.