Advancements in PARP Inhibition: The Emergence of IDX-1197 as a Promising Therapeutic Agent

PARP inhibitors have shown significant benefits in progression-free survival for patients with recurrent ovarian cancer, especially following treatment with platinum-based chemotherapy. However, their efficacy is limited in non-germline BRCA-mutated patients. A new PARP inhibitor, IDX-1197, has been developed to potentially enhance antitumor efficacy in both germline and non-germline BRCA-mutated patients.

IDX-1197 was evaluated in vitro using PARP enzyme assays and catalytic inhibition assays in Hela cells. Its in vivo efficacy was assessed in patient-derived xenograft (PDX) models of ovarian and breast cancer. The inhibitor's impact on tumor PAR levels was measured using ELISA in PDX models.

Results demonstrated that IDX-1197 effectively inhibited PARP1 and PARP2 with IC50 values of 1.4 nM and 1.0 nM, respectively, while showing no significant effect on PARP5A (Tankyrase-1). In DNA damage-induced Hela cells, IDX-1197 markedly reduced PAR expression mediated by PARP1. In a germline BRCA1-mutated ovarian cancer PDX model, IDX-1197 showed significant PAR inhibition in tumor tissues up to 24 hours post-dose and potent tumor growth inhibition in a dose-dependent manner, outperforming Olaparib.

Moreover, IDX-1197 displayed improved antitumor activity against breast cancer PDX models, including both germline and non-germline BRCA-mutated cases. It exhibited greater tumor growth inhibition compared to both Olaparib and Niraparib.

In conclusion, IDX-1197 is a highly potent and selective PARP1/2 inhibitor with significant in vitro and in vivo activities across multiple cancer models. The preclinical data suggest that IDX-1197 has the potential to be a best-in-class PARP inhibitor, effective for both non-germline BRCA-mutated and BRCA-mutated patients. IDX-1197 has since entered a phase 1 clinical trial in Korea, supported by National OncoVenture.

The research was presented by Myongjae Lee and colleagues at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics in 2017.