Abstract 1765: RPT1G, a first-in-class hyperbolic NAMPT inhibitor that avoids on-target toxicity

Abstract Therapeutic inhibition of NAD+ synthesis has been challenging to achieve in the clinic due to severe on-target toxicity stemming from the critical role of NAD+ in living systems. The elevated energy requirements of cancer cells necessitate increased NAD+ recycling through the nicotinamide phosphoribosyltransferase (NAMPT) salvage pathway. Drug candidates have attempted to reduce NAD+ in cancer cells by complete inhibition of NAMPT, resulting in systemic, dose-limiting toxicity. RPT1G is a first-in-class hyperbolic inhibitor that significantly reduces, but does not eliminate, NAMPT activity. This unique mechanism-of-action reduces NAD+ below survival thresholds in cancer cells while allowing survival of healthy tissues, manifest by limited on-target toxicity in GLP studies and robust therapeutic efficacy in multiple oncological models. RPT1G has been approved to start clinical testing in healthy volunteers. This first-in-human study will determine the safety and pharmacokinetics of hyperbolic NAMPT inhibition while measuring metabolic changes resulting from reduced NAMPT activity. RPT1G represents the first hyperbolic NAMPT inhibitor to be tested in humans, opening opportunities to therapeutically modulate NAD+ synthesis and providing a roadmap for the development of hyperbolic inhibitors of other essential enzyme targets. Citation Format: Gregory Thomas Crimmins, Min Wu, Timothy Jarvela, Yushma Bhurruth-Alcor, James Digel, Francis Roushar, Dexter Davis, Caroline M. Robb, Michael Schelle, Banumathi Cole, Frank McCormick, Dennise A. De Jesús-Díaz. RPT1G, a first-in-class hyperbolic NAMPT inhibitor that avoids on-target toxicity [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 1765.