Abstract 6972: Discovery of XNW29016, a PARG inhibitor for HRD cancer therapy
Authors: Yonghan Hu, Haiyang Wei, Dawei Wan, Ben Ma, Jiajing Xu, Shihua Wang, Liang Kong, Zhe Zhang, Yuanbao Li, Zhenwei Wu, Yuzhen Hou, Wengui Wang, Xiaojun Liu, Meijie Le, Jing Qiang
Journal: Cancer Research (2025)

Abstract DNA damage repair enzymes are promising targets as genomic instability and DNA repair defects are important characteristics of cancer cells PARylation catalysed by PARP1/2 is a kind of reversible protein modification, which has central functions in maintaining genome stability. Poly (ADP-Ribose) glycohydrolase (PARG) is the dominant eraser of PARylation in the cell, whose activity prevents excessive accumulation of PARylation, promotes the dissociation of repair proteins, and ensures the smooth completion of DNA repair process. Deficiency of PARG leads to accumulation of PARylation and deregulation of DNA repair, which in turn causes cells to be sensitive to DNA damage and replication stress. So PARG is considered as a promising target for treating tumors characterized by DNA repair defects. PARG and PARP are in the same biochemical pathway, but their inhibitors inhibit tumor cell growth through different mechanisms, and therefore tumor cells show different sensitivities to the two inhibitors. Since the efficacy of PARP inhibitors is limited by intrinsic or acquired drug resistance in clinical practice, PARG inhibitors can also be used as an effective supplement for PARP inhibitors. XNW29016 is a rationally designed PARG inhibitor which binds directly to the PARG catalytic domain with in vitro biochemical IC50 of 29nM against PARG. Treating cells with XNW29016 strongly induced the accumulation of intracellular PARylation, activated DNA damage response signaling pathway and caused cell cycle arrest. XNW29016 demonstrated potent in vitro antitumor effects in a variety of PARPi-resistant cancer cell lines such as RMUG-S, KURAMOCHI and HCC1428. SNU601 and HCC1806 cells with acquired niraparib resistance or carboplatin resistance continued to be sensitive to XNW29016, but insensitive to niraparib. This result indicates that patients could still benefit from XNW29016 after treatment with PARP inhibitors and platinum drugs. In line with in vitro activities, XNW29016 performs antitumor activity in cell derived xenograft models of breast cancer, ovarian cancer, and gastric cancer. In vivo efficacy is dose-dependent and test dosages are well-tolerated, with minimum effective dose at 25 mg/kg/dose twice daily. We observed a time-dependent accumulation of PARylation. XNW29016 has good oral bioavailability and excellent exposure in preclinical pharmacokinetic studies. In toxicological studies, XNW29016 exhibits satisfactory safety profile. Altogether, these preclinical findings warrant further clinical evaluation of XNW29016 in patients with HRD cancers. Citation Format: Yonghan Hu, Haiyang Wei, Dawei Wan, Ben Ma, Jiajing Xu, Shihua Wang, Liang Kong, Zhe Zhang, Yuanbao Li, Zhenwei Wu, Yuzhen Hou, Wengui Wang, Xiaojun Liu, Meijie Le, Jing Qiang. Discovery of XNW29016, a PARG inhibitor for HRD cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6972.