QLS1403：一种新型高效 PARG 抑制剂，在同源重组缺陷癌症模型中具有强效抗肿瘤疗效

Background: Cancer cells experience high levels of endogenous replication stress due to persistent proliferative signaling. Poly (ADP-ribose) polymerase (PARP) is a first responder to DNA damage, catalyzing the synthesis of poly (ADP-ribose) (PAR) chains that serve as docking platforms for DNA repair proteins. The hydrolysis of these PAR chains, a critical step for the turnover of repair complexes, is primarily mediated by poly (ADP-ribose) glycohydrolase (PARG). Pharmacological inhibition or genetic loss of PARG prevents PAR chain hydrolysis, which results in persistent stalling of replication fork, nucleolytic degradation of nascent and parental DNA and ultimately cell death. IDE-161, a first-in-class PARG inhibitor has entered clinical trials. This study reports the discovery and characterization of QLS1403, a proprietary PARG inhibitor designed to selectively treat homologous recombination deficient (HRD) cancers, particularly those resistant to PARP inhibitors (PARPi) or T-Dxd. Experimental Procedures: The activities of QLS1403 were characterized by biochemical PARG inhibition assay, cellular viability assessment in HRD-positive and PARPi-resistant or T-Dxd-resistant cancer cell lines and in vivo evaluation of efficacy in ovarian and breast cancer xenograft models. In addition, the pharmacodynamic effect, i.e., the PAR chain accumulation and its pharmacokinetic properties were assessed in both cells and animals. Results: QLS1403 demonstrated exceptional PARG inhibitory activity (IC₅₀ = 0.35 nM) and remarkable cellular activity in HRD-positive cancer cell lines, showing approximately 10-fold greater potency than IDE-161. Notably, QLS1403 showed strong activity in PARPi- or T-Dxd-resistant cell lines. Also, QLS1403 caused tumor regression at lower doses across multiple xenograft models with intrinsic PARPi resistance, accompanied by dose-dependent PAR accumulation in tumors. In addition, QLS1403 exhibited a clean selectivity and safety profile in vitro , with no significant off-target activity observed in safety assessment panels. Conclusion: QLS1403 demonstrates superior potency, sustained efficacy in PARPi-resistant and T-Dxd-resistant cancer cell lines, while displaying favorable safety. These compelling data support its clinical evaluation as a new therapeutics for patients with HRD-positive cancers with acquisition of resistance to PARPi or potentially other existing treatments, such as T-Dxd.