Abstract title | Preclinical profile of novel and potent small molecule inhibitors of PARG |
Poster number | 7112 |
Session title | DNA Damage and Repair |
Session date and time | April 10, 9:00 AM - 12:30 PM |
Session category | Experimental and Molecular therapeutics |
Abstract title: Preclinical profile of novel and potent small molecule inhibitors of PARG
Abstract:Poly(ADP-ribose) glycohydrolase (PARG) is primary enzyme involved in the dePARylation process of DNA repair, specifically in the single strand break repair (SSBRs). PARG is a macrodomain protein with exo- and endo-glycohydrolase activity that liberates free ADP-ribose and PAR chains, respectively. It interacts with various Poly(ADP-ribose) polymerase (PARP) proteins to facilitate appropriate and timely DNA repair. The balance between PARP and PARG activity is essential for efficient DDR. Inhibition of PARG lead to altered DNA repair in cancer cells. We have identified highly potent PARG inhibitors with picomolar IC50 in biochemical assay. PARG is the primary enzyme for dePARylation and accounts for 90% of dePARylation activity. Treatment of HCC-1806 cells with PARG inhibitors showed dose dependent increase of PARylation signature, with sub micromolar IC50 . Compounds also demonstrate significant functional, anti-proliferative activity in ovarian and breast cancer cell lines besides a favourable ADME profile. Further pharmacokinetic and pharmacodynamic characterization of the identified hits is currently in progress.
