92 (PB082) - RP12146, a novel, selective, and potent small molecule inhibitor of PARP 1/2, synergizes with SOC therapy in preclinical models of solid tumors

Abstract

Background: Poly (ADP-ribose) polymerase (PARP) activity involves synthesis of Poly-ADP ribose (PAR) polymers that recruit host DNA repair proteins leading to correction of DNA damage and maintenance of cell viability. Several PARP inhibitors have been approved for the treatment of BRCA-mutated ovarian, breast and pancreatic cancer. In addition to BRCA-mutated cancers, therapeutic role of PARP inhibitors as monotherapy agent or in combination with established therapy can be expanded to other types of solid tumors through ‘synthetic lethality’ mechanism. Herein, we describe the efficacy of RP12146 as a single agent and in combination with approved therapies in preclinical models of solid tumors. Material & Methods: Enzymatic potency was evaluated using a PARP Chemiluminescent Activity Assay Kit (BPS biosciences). Cell growth was determined following incubation with RP12146 as a single agent or in combination with approved agents in various solid tumor cell lines. Apoptosis & Cell cycle was evaluated following incubation of cell lines with compound for 48 or 72 h, subsequent staining with Annexin-V-PE and 7-AAD or Propidium Iodide, and analysis by flow cytometry. Anti-tumor potential of RP12146 as a single agent or in combination with chemotherapeutic agents was tested in OVCAR-3 and NCI-H69 Xenografts. Expression of downstream markers were determined in cell lines and xenograft tumor samples by Western blotting. Results: RP12146 inhibited PARP1 (0.6 nM) & PARP2 (0.5 nM) with equal potency with several fold selectivity over the other members of the PARP family. In addition, RP12146 demonstrated selective PARP1-Trapping with ∼20-fold selectivity over PARP2. RP12146 caused a dose-dependent growth inhibition of both BRCA mutant and non-mutant cancer cell lines with GI50 in the range of 0.04 μM to 9.6 μM. Combination of RP12146 with Temozolomide, SN-38, Topotecan, and Lurbinectedin demonstrated either additive or synergistic effects manifested by an inhibition in growth, induction of apoptosis and cell cycle arrest in Breast, Gastric, Glioma, Lung Cancer, and Ovarian cancer cell lines. RP12146 exhibited anti-tumor potential with TGI of 28% and 21.8% as a single agent in OVCAR-3 and NCI-H69 Xenograft model respectively. In NCI-H69 xenograft model, RP12146 in combination with cisplatin exhibited TGI of 69.3%. Conclusion: Data demonstrate the therapeutic potential of RP12146 as single agent and in combination in solid tumors. RP12146 is currently being evaluated in Phase 1 clinical trials in patients with locally advanced or metastatic solid tumors (NCT05002868). No conflict of interest.