Abstract 5720: Novel selective FEN1 nuclease inhibitor shows synergy with PARP-targeting drugs

Abstract Tumors with homologous recombination defects (HRD) due to mutations in BRCA1/2 genes or other genes associated with HR repair are typically sensitive to poly(ADP-ribose) Polymerase 1/2 inhibitors (PARPi), platinum-based drugs or other agents that target DNA repair pathways. Despite initial responsiveness to PARPi, many patients eventually experience disease progression. To that end, novel drug combination strategies involving PARPi plus other DNA replication and repair inhibitors have the potential to achieve more durable responses. Flap endonuclease 1 (FEN1) is a structure-specific metallonuclease that has been shown to be overexpressed in a variety of tumor types and has been reported to have many synthetic lethality partners, including PARP and BRCA2, making it an attractive target for the development of novel anticancer therapeutics. Utilizing an innovative library of metal-binding pharmacophores (MBPs) and a fragment-based drug discovery approach we identified a novel FEN1-selective chemical scaffold represented by BSM-1516 (IC50 of 7 nM and 460 nM in biochemical assays for FEN1 and EXO1, respectively; FEN1 cellular thermal shift target engagement assay EC50 of 24 nM). Examination of proteins on replication forks by iPOND-SILAC-MS in the presence of BSM-1516 revealed rapid enrichment of Okazaki fragment maturation (OFM) proteins FEN1/PCNA/LIG1, PARP1/2 enzymes, poly(ADP-ribose) binders (e.g. CHD1L) and alternative OFM pathway repair proteins XRCC1 and LIG3. Combination of BSM-1516 with inhibitors of PARP1/2 was strongly synergistic in vitro, enhanced their antiproliferative effect up to 100-fold (an effect not observed in normal fibroblasts) and led to robust activation of ssDNA break repair markers: phospho-Chk1(Ser345), phospho-RPA2(Ser33) and chromatin-bound RPA2. In vivo PK studies showed that BSM-1516 had oral bioavailability of 40% and T1/2 of 2.9 hours in mice. Safety of BSM-1516 was assessed in vitro in lineage-specific differentiation of human hematopoietic CD34+ progenitor cells and in vivo in mice at a daily dose of 120 mg/kg PO and 90 mg/kg IP for 7 days and revealed no signs of hematological toxicity. These collective data support further in vivo testing in PD and efficacy studies either as a single agent or in combination with PARPi. Citation Format: Jason Munguia, Sanjay Agarwalla, Dave Martin, Junhua Fan, Dave Lonergan, Celeste Giansanti, David Cortez, David Puerta, Zachary Zimmerman, Konstantin Taganov. Novel selective FEN1 nuclease inhibitor shows synergy with PARP-targeting drugs [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 5720.