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

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.