Abstract 1748: FORX-428: Exploiting PARG inhibition to target replication stress in cancer cells

Abstract PARylation/dePARylation is essential for sensing and repairing replication-associated DNA damage. Inhibitors of the PARP enzymes catalyzing the build-up of poly(ADP-ribose) chains have become a mainstay of breast and ovarian cancer therapy over the past decade. Inhibiting PARG, the enzyme responsible for degrading poly(ADP-ribose) chains, has rapidly gained momentum as a therapeutic approach to benefit cancer patients which develop resistance to PARP inhibitor therapy. FORX-428 is a highly potent, reversible, selective, and orally bioavailable PARG inhibitor with the expected mechanism of action and exquisite efficacy in PARP inhibitor-resistant cancers. Of note, PARG inhibition demonstrated un-precedented antitumor activity in cancers with oncogene-induced replication stress suggesting therapeutic potential even outside of the label of PARP inhibitors. FORX-428 entered a Phase 1 clinical trial in July 2025. We will present the structure of FORX-428, in-depth pharmacology data as well as up-to-date results from the ongoing Phase 1 study. Collectively, these findings provide evidence supporting PARG inhibition as a novel and promising therapeutic strategy to treat PARP inhibitor-resistant and other hard-to-treat cancers. Citation Format: Frank Tadashi Zenke, Ulrich Lücking, Olivier Querolle, Luca Iacovino, Marta Malattia, Alessandro Potenza, Nicolas Bocquet, Serena Bologna, Hanna Kok, Anika Kuster, Roxanne Lourman, Jason Clochard, Irena Konstantinova, Thanos D. Halazonetis, Jens Wuerthner, Tarig Bashir. FORX-428: Exploiting PARG inhibition to target replication stress in cancer cells abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1748.