Abstract 4263: QX-001352 is a novel and specific inhibitor of PARG with potentially BIC in vitro and in vivo anti-tumor efficacy

Abstract When DNA is damaged one of the critical steps is the addition of Poly-ADP-ribose (PAR) chains to target proteins. Poly ADP-ribose polymerase 1 (PARP1) is an enzyme that adds PAR chains to target DNA repair proteins including itself. This serves as a recruitment signal for other DNA repair enzymes to localize to the site of DNA damage. Poly ADP-ribose glycohydrolase (PARG) has a crucial role in DNA repair. This role is by virtue of its intrinsic enzymatic activity to catalyze the removal of PAR chains from target proteins. This removal leads to the resolution of DNA strand breaks. When PARG is inhibited or its expression is abrogated, PAR chains go unresolved and therefore DNA lesions also. This leads to genomic instability and cell death. Therefore, there is a critical balance of PAR chains which is reciprocally regulated by PARP1 and PARG and perturbing this balance may negatively affect tumor cell growth. This makes PARG a rational drug target in oncology, against which the compound QX-001352 has been developed as a potentially best in class (BIC) inhibitor. QX-001352 is a potent inhibitor of PARG. QX-001352 was shown to inhibit the removal of PAR chains from PARylated PARP1 with an IC50 of 0.2 nM in a biochemical assay. This suggests QX1352 is a potent inhibitor of PARG.QX-001352 was able to inhibit the growth of two ovarian tumor cell lines as well as a breast and gastric tumor cell line. The IC50’s ranged from 1.5 nM to 11.9 nM indicating potent cell growth inhibition which represents around 10 folds more potent activity than a benchmark compound in the clinic. QX-001352 blocked the removal of PAR chains in Kuramochi cells in dose dependent manner with an IC50 of 0.1 nM indicating excellent target engagement. In vivo in a Kuramochi cell xenograft model, QX-001352 caused robust tumor regression. Both low and high doses of QX-001352 were fully efficacious whereas no effect was seen with vehicle treated animals. QX-001352 was well tolerated in all the treated groups. In conclusion, QX-001352 is a potent and specific inhibitor of PARG. This inhibition leads to PAR chain accumulation and prevents tumor cell growth both in vitro and in vivo. QX-001352 possesses highly desirable physicochemical properties and demonstrated favorable off-target profiles. Thus QX-001352 may be an effective PARG inhibitor in the clinic. Citation Format: Dafydd Thomas, Xianhai Huang, Vijay Reddy, Wayne Tang. QX-001352 is a novel and specific inhibitor of PARG with potentially BIC in vitro and in vivo anti-tumor efficacy [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 4263.