Abstract 3366: FoRx-06-428 is a novel PARG inhibitor with potent anti-tumor efficacy in preclinical cancer models

Abstract

Abstract The formation of poly(ADP-ribose) (PAR) chains from NAD+ precursors by PARP enzymes is a characteristic posttranslational modification during DNA damage repair. PAR chains function as docking platforms for DNA repair proteins that are required to resolve DNA lesions. Equally important is the subsequent removal of PAR chains from protein substrates to conclude the repair process and restore genomic integrity. Poly(ADP-ribose) glycohydrolase (PARG) is the key enzyme in this process and has recently garnered significant attention as a novel cancer target. FoRx-06-428 is a novel, orally bioavailable and highly potent, low molecular weight PARG inhibitor. It binds to the catalytic domain of human PARG with high affinity, as evidenced by surface plasmon resonance (SPR), and displays potent inhibition of enzymatic activity. FoRx-06-428 shows selective reduction of viability in a panel of cancer cell lines highlighting therapeutic potential in multiple cancer indications. Pharmacological inhibition of PARG leads to accumulation of PAR chains and is indicative of target engagement, accompanied by modulation of DNA damage response markers, such as phosphorylation of replication protein A (pRPA) and phosphorylation of H2AX (γH2AX). Compelling anti-tumor efficacy as single agent was observed in several xenograft models (breast and gastric cancer) with excellent tolerability. Dose-dependent accumulation of PAR chains was demonstrated in vivo and constitutes a tractable target engagement biomarker for clinical exploration. Sensitivity to PARG inhibition is partly driven by distinct genomic instabilities, such as defects in homologous recombination (HR) repair, however the activity of PARG inhibitors is also influenced by aberrations in other cancer-relevant pathways. This report represents the first disclosure of the pharmacological characterization of FoRx-06-428 and highlights the value of PARG inhibition as a novel targeted approach to treat DNA repair-deficient cancers. Citation Format: Olivier Querolle, Ulrich Lücking, Luca Iacovino, Alena Freudenmann, Giacomo Rossetti, Marina Gysin, Serena Bologna, Vasilis Dionellis, Marta Malattia, Alessandro Potenza, Nicolas Bocquet, Irena Konstantinova, Andreas Goutopoulos, Sotirios Sotiriou, Thanos Halazonetis, Tarig Bashir, Frank Zenke. FoRx-06-428 is a novel PARG inhibitor with potent anti-tumor efficacy in preclinical cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3366.