RPT1G: A 1 st-in-Class Small Molecule NAMPT Inhibitor As a Novel Therapeutic for Acute Lymphocytic Leukemia

• Published in: Blood 2023-11, Vol.142 (Supplement 1), p.419-419
• Main Authors: Crimmins, Gregory, Bhurruth-Alcor, Yushma, Jarvela, Timothy, Wu, Min, Robb, Caroline M., Digel, James, Moghaddam-Taaheri, Parisa, De Jesús-Díaz, Dennise A.
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2023-189691

Nicotinamide phosphoribosyltransferase (NAMPT) catalyzes the rate limiting step in the nicotinamide adenine dinucleotide (NAD +) salvage pathway: the conversion of nicotinamide and 5-phosphoribosyl-1-pyrophosphate into nicotinamide mononucleotide. Because NAMPT plays a central role in cancer metabolism (e.g., Warburg effect) and is upregulated in many hematologic malignancies, it is a high-value target for oncology applications. Despite promising preclinical data showing the potential of complete NAMPT inhibitors (NAMPTi) as effective oncology agents, early clinical trials yielded limited benefit due to the small therapeutic window for the agents tested. Complete NAMPT deactivation disrupts essential biological pathways in both cancer and healthy cells, and hence could not induce efficacy without causing dose-limiting toxicities. Here we introduce a novel partial NAMPTi, RPT1G, which was optimized to allow residual activity to meet the metabolic needs of healthy cells and to overcome the challenge of on-target toxicity. RPT1G's 1 st-in-class mechanism of action (MOA) simultaneously inhibits and stabilizes NAMPT in a catalytically active state, disrupting NAMPT enzymatic activity without ever turning it off. RPT1G achieves significant efficacy in a B-cell acute lymphoblastic leukemia (B-ALL) mouse xenograft model and avoids the severe on-target toxicities seen with complete NAMPTi. To demonstrate the importance of NAMPT residual activity in preserving cellular metabolism in healthy cells, we determined the mitochondrial respiration rate for RS4;11 (B-ALL) and human peripheral blood mononuclear cells (huPBMCs) treated with RPT1G. The oxygen consumption rate (OCR) markedly decreased in treated RS4;11 cells, consistent with RPT1G-induced inhibition of cellular bioenergetics. In contrast, in huPBMC, increasing concentrations of RPT1G elicited a dose-dependent decrease of OCR, up to a concentration equal to 5-fold the IC50 in RS4;11, beyond which, further reductions in OCR were not observed. This indicates that RPT1G's influence on mitochondrial respiration had reached its maximum effect, consistent with huPBMCs being able to use their reserve capacity to maintain cell survival. To further validate the novel MOA of RPT1G in vivo, we tested the viability of >100 cancer cell lines as well as huPBMCs upon RPT1G treatment. Leukemias, specifically ALL cells, displayed high sensitivity to RPT1G. Also, the concentrations required to achieve >90% NAD + reduction in RS4;