Abstract B022: FORX-428: A best-in class PARG inhibitor with promising anti-tumor activity in preclinical cancer models

Abstract The formation of poly (ADP-ribose) (PAR) chains from NAD+ catalyzed by PARP enzymes is a pivotal posttranslational modification at sites of DNA lesions or stalled replication forks and serves as a scaffold to recruit DNA repair proteins. Equally important as the formation is the degradation of PAR chains to conclude DNA repair and maintain genomic integrity. Poly (ADP-ribose) glycohydrolase (PARG) plays a key role in this degradation process and has recently been identified as a promising target for cancer therapy. FORX-428 is a highly potent, selective and orally bioavailable PARG inhibitor. It exhibits strong and reversible binding to the catalytic domain of human PARG, confirmed by X-ray crystallography, and thereby inhibits PARG´s enzymatic activity. Inhibition of PARG by FORX-428 leads to the excessive accumulation of PAR chains and activates the DNA damage and replication stress response. FORX-428 selectively inhibits the proliferation of various cancer cell lines, suggesting strong therapeutic potential across multiple cancer types when guided by biomarkers predictive of patient response to PARG inhibition. Sensitivity to PARG inhibition is driven by alterations in the DNA damage response, such as defects in homologous recombination and oncogene-induced replication stress. FORX-428 monotherapy demonstrated strong anti-tumor efficacy across multiple CDX and PDX models, including breast, ovarian, and gastric cancer with best-in-class potential compared to advanced clinical PARG and approved PARP inhibitors. Here, we present the in-depth pharmacological characterization of FORX-428 which has recently received IND clearance and entered clinical development. PARG inhibition represents a novel and highly promising strategy for the treatment of cancers harboring specific vulnerabilities in the DNA damage response. Citation Format: Frank Tadashi. Zenke, Ulrich Lücking, Olivier Querolle, Andreas Goutopoulos, Luca Iacovino, Marta Malattia, Alessandro Potenza, Nicolas Bocquet, Alena Freudenmann, Serena Bologna, Vasilis Dionellis, Giacomo Rossetti, Marina Gysin, Hanna Kok, Roxanne Lourman, Jason Clochard, Anika Kuster, Irena Konstantinova, Sotirios Sotiriou, Thanos Halazonetis, Jens Würthner, Tarig Bashir. FORX-428: A best-in class PARG inhibitor with promising anti-tumor activity in preclinical cancer models [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr B022.