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.