RPT1G, a novel hyperbolic NAMPT inhibitor, effectively synergizes with PARP inhibitors in solid tumors in vitro and in a xenograft breast cancer model

Background: Poly-ADP ribose polymerase (PARP) inhibitors are key drugs in treating solid tumor patients with defects in homologous DNA repair (HR) pathways. The substrate for PARP enzyme activity, nicotinamide adenine dinucleotide (NAD), is regulated by nicotinamide phosphoribosyltransferase (NAMPT), the rate limiting enzyme in NAD recycling. NAMPT is upregulated in many cancers, in part to supply the NAD consumed by PARP enzymes. RPT1G is a novel hyperbolic NAMPT inhibitor that eliminates NAD in cancer cells while allowing NAD production in healthy tissues. The safety, tolerability, and NAMPT inhibition of RPT1G was recently demonstrated in a first-in-human Phase 1 study (NCT06667765, Crimmins et al., ASH 2025). Here we show that RPT1G synergizes with PARP inhibitors in solid tumor cells and in a xenograft breast cancer model. Methods: Cells were incubated with RPT1G, olaparib, or in combination for 96 hours then assessed for viability using CellTiter Glo. MDA-MB-436 mouse xenograft studies testing RTP1G, olaparib, or combination were initiated when the average tumor size reached 150-200 mm 3 . Results: RPT1G in combination with the PARP inhibitor olaparib was synergistic across a spectrum of solid tumor cell lines, including breast, pancreatic, and ovarian cancers. Several solid tumor cell lines that are resistant to either RPT1G or olaparib monotherapy showed increased sensitivity to RPT1G and olaparib combinations, including Cal51 (breast) and Mia Paca-2 (pancreatic). Similarly, the MDA-MB-436 triple negative HR-deficient breast cancer xenograft model was insensitive to RPT1G monotherapy, while combination of RPT1G with olaparib synergistically inhibited tumor growth, with complete tumor elimination in 40% of the mice versus <15% with olaparib monotherapy. Furthermore, 80% of mice treated with olaparib monotherapy rebounded despite continuous treatment, compared with <40% of mice showing tumor rebound when treated with RPT1G and olaparib. Conclusion: Therapeutic inhibition of NAD synthesis with NAMPT inhibitors has been challenging to achieve clinically due to severe on-target toxicity stemming from the critical role of NAD in living systems. RPT1G is the first NAMPT inhibitor that is well-tolerated in people. The high tolerability of RPT1G is especially critical when combining with PARP inhibitors that have known toxicities. We demonstrate that RPT1G in combination with olaparib is efficacious and synergistic in breast, pancreatic, and ovarian solid tumors in vitro , and enhances the extent and duration of efficacy in an HR-deficient mouse xenograft breast cancer model. Thus, we present a novel combination strategy to overcome the challenges seen with approved monotherapies in solid tumors.