• March 21, 2024

• 4:10 am

Satya to present preclinical profile of its PARG inhibitors at the 2024 American Association for Cancer Research (AACR) Annual Meeting – April 5-10, San Diego, CA

Abstract Title

Preclinical profile of novel and potent small molecule inhibitors of PARG

Abstract

Poly(ADP-ribose) glycohydrolase (PARG) is the primary enzyme involved in the dePARylation process of DNA repair, specifically in single strand break repair (SSBR). PARG is a macrodomain protein with both exo- and endo-glycohydrolase activity that liberates free ADP-ribose and PAR chains, respectively.

The enzyme 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 DNA damage response (DDR). Inhibition of PARG leads to altered DNA repair mechanisms in cancer cells.

We have identified highly potent PARG inhibitors demonstrating picomolar IC₅₀ values in biochemical assays. As the primary enzyme for dePARylation, PARG accounts for approximately 90% of total dePARylation activity. In HCC-1806 cell lines, PARG inhibitors showed dose-dependent increases in PARylation signature with sub-micromolar IC₅₀ values.

These compounds exhibit significant functional anti-proliferative activity in both ovarian and breast cancer cell lines, while maintaining favorable ADME profiles. Current research focuses on further pharmacokinetic and pharmacodynamic characterization of these candidate molecules.