Abstract 419: Targeting NAMPT using Novel Inhibitor RPT-E-037 in Pancreatic Neuroendocrine Tumor.

Abstract Background and Objective: Advanced pancreatic neuroendocrine tumors (pNETs) respond poorly to current FDA-approved therapies, emphasizing the urgent need to find new and effective treatment targets. Nicotinamide phosphoribosyltransferase (NAMPT), a key enzyme in the NAD biosynthesis pathway, has emerged as a crucial therapeutic target in pNETs. Despite its importance, specific inhibitors directly targeting NAMPT for pNET treatment are currently lacking. This study aimed to evaluate the efficacy of RPT-E-037, a novel NAMPT inhibitor, in preclinical models of pNETs. Methods: Growth inhibition was determined by MTT, colony formation and apoptosis assays. We also measured growth arrest using cell cycle analysis. Expression of gene or protein was determined using quantitative PCR, and western blotting techniques. The impact of NAMPT inhibitor RPT-E-037 was evaluated in pNET in vitro cultures and in in vivo. Results: RPT-E-037 demonstrated its growth inhibitory effect in BON-1 and QGP-1 pNET cell lines at pharmacologically relevant concentrations. The inhibitory concentration-50 (IC50) were determined as 0.3 and 1.2 micromolar (µM) in BON-1 and QGP-1 cells respectively. Importantly, RPT-E-037 demonstrated selectivity, showing no adverse effects on normal islet cells (ABC-TC4286, AcceGen) at concentrations effective against tumor cells (reflected by its 40-folds higher IC50). In addition, growth inhibitory effect of RPT-E-037 significantly rescued by nicotinic acid (niacin) treatment in BON-1 cells. Niacin also diminishes its colony reduction and apoptotic ability of RPT-E-037 in this cell line. The novel NAMPT inhibitor RPT-E-037 was shown to induce “DNA synthesis (S) phase” cell cycle arrest. However, niacin treatment switches “S phase” cell cycle arrest to “G0/G1 phase” cell cycle arrest. RPT-E-037 synergized with pNETs standard of care mTOR targeted agent everolimus in both BON-1 and QGP-1 cell lines leading to superior cell deaths (CI1). The in vivo efficacy of RPT-E-037 in BON-1 and QGP-1 cell line derived xenografts (CDxs) are under way. Conclusion: For the first time, this study reveals the therapeutic potential of RPT-E-037, a new NAMPT inhibitor, for pNETs in preclinical models. RPT-E-037 shows promise as a novel NAMPT inhibitor and deserves further clinical investigation for pNETs.Generative AI was used for improving the language of the abstract. Citation Format: Md Hafiz Uddin, Husain Yar Khan, Amro Aboukameel, Sahar F. Bannoura, Irfana Muqbil, Hugo Jimenez, Filza Khan, Rafic Beydoun, Gregory Dyson, Yang Shi, Mohammed N. Al Hallack, Nitin Vaishampayan, Ibrahim Azar, Steve Kim, Eliza W. Bael, Miguel Tobon, Khalil Choucair, Walid Sukkari, Hafsa Imtiaz, Herbert Chen, Muhammad W. Saif, Anthony Frank Shields, Ramzi M. Mohammad, Philip Philip, Bassel F. El Rayes, Min Wu, Michael Schelle, Boris Pasche, Asfar S. Azmi. Targeting NAMPT using Novel Inhibitor RPT-E-037 in Pancreatic Neuroendocrine Tumor abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 419.