LAUSR

Background: PARP inhibitors have demonstrated clinically meaningful increase in progression-free survival as a single agent in women with recurrent ovarian cancer following a response to platinum-based chemotherapy. However, there still needs more improvement in efficacy because PARP inhibitors have comparatively low efficacy in non-germline BRCA-mutated patients. We aimed to develop a novel PAPR inhibitor that may have potent antitumor efficacy against the non-germline BRCA-mutated patients in addition to the germline BRCA-mutated patients. Here, we describe a novel selective PARP inhibitor IDX-1197. Materials and Methods: We conducted in vitro assays to evaluate IDX-1197 as a PARP inhibitor using PARP enzyme assay and PARP-catalytic inhibition assay in Hela cells. We evaluated in vivo efficacy of IDX-1197 against ovarian and breast tumor growth using patient-derived xenograft models. To investigate PARP inhibition in tumors, tumor PAR levels were measured by ELISA in the PDX models. Results: In enzyme assay, IDX-1197 potently inhibited PARP1 and PARP2 activities with IC50 values of 1.4 nM and 1.0 nM, respectively. By contrast, IDX-1197 was not sensitive to PARP5A (Tankyrase-1), which belongs to the PARP family (IC50>10 μM). In DNA damage-induced Hela cells, IDX-1197 significantly inhibited PARP1-mediated PAR expression (EC50 = 0.5 nM). In the germline BRCA1-mutated ovarian cancer PDX model, oral administration of IDX-1197 exhibited significant PAR inhibition (>90%) in tumor tissues until 24 hr post dose. IDX-1197 also dose-dependently led to potent tumor growth inhibition compared to Olaparib treatment group. Furthermore, IDX-1197 showed improved antitumor activity against breast cancer PDX models, which included both germline BRCA-mutated and non-germline BRCA-mutated models. In these models, IDX-1197 exhibited greater tumor growth inhibition compared with olaparib and/or niraparib. Conclusions: IDX-1197 is a highly potent and selective inhibitor of PARP1/2 with significant in vitro and in vivo activities in multiple cancer models. These preclinical data demonstrate the efficacy of IDX-1197, which has the potential for a best-in-class profile, in non-germline BRCA-mutated patients as well as BRCA-mutated patients. Based on these findings, IDX-1197 has entered clinical phase 1 trial in Korea. Funded by National OncoVenture. Citation Format: Myongjae Lee, Joon-Tae Park, Ji-hun Yang, Dohee Kim, In-Gyu Je, Yoon Suk Lee, Jinah Jeong, Dong Keun Song, Soobong Park, Hong-Sub Lee, Yong-Man Kim, Shin-Wha Lee, Dong Woo Kang, Ha-Young Lee, Jung Yong Kim, Sungsook Lee, Nam Seok Baek, Jae-Hoon Kang. Development of IDX-1197, a novel, selective, and highly potent PARP inhibitor [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A106.