Abstract 1049: Pharmacological characterization of a novel potent nicotinamide phosphoribosyltransferase (NAMPT) inhibitor with robust in vivo efficacy and increased therapeutic index with niacin supplementation

Abstract

Nicotinamide adenine dinucleotide (NAD+) is an important metabolite and cofactor for a number of cellular processes including genomic stability and epigenetic regulation. Nicotinamide phosphoribosyltransferase (NAMPT) is the rate limiting enzyme in NAD+ salvaging from nicotinamide. Many tumor cells have an increased need for NAD+ and are therefore highly sensitive to NAMPT inhibition. We have developed a selective and potent small molecule inhibitor, Cmpd1, which inhibits the NAMPT enzyme with sub-nanomolar potency. In cells, Cmpd1 treatment leads to an almost complete reduction of both NAD- and ATP-levels, followed by the induction of cell death. In order to identify sensitive cancer subtypes and associated biomarkers, we analyzed cell sensitivity to NAMPT inhibition in a panel of 240 cell lines. Small cell lung cancer and hematological malignancies were particularly sensitive to NAMPT inhibition. Overall, expression levels of NAMPT and NAD+ consuming enzymes correlated well with sensitivity to NAMPT inhibition.

In order to investigate the effect of niacin on the antiproliferative effect of NAMPT inhibition across the cell panel, we further analyzed the cell sensitivity in the presence of niacin. Cells with a functional Preiss-Handler pathway can generate NAD+ from niacin, independent of NAMPT. We found that the antiproliferative effect of Cmpd1 was neutralized by niacin in 60% of the analyzed cells. The mRNA levels of nicotinate phosphoribosyltransferase 1 (NAPRT1), a central enzyme of the Preiss-Haendler pathway, predicted well the niacin rescue status of the cells. In vivo, niacin supplementation led to an at least 10-fold increase in the maximum tolerated dose of Cmpd1 in mice. Antitumor efficacy of Cmpd1 was abolished by niacin supplementation in xenografts derived from NAPRT1 expressing cells, but not in NAPRT1-deficient models. These data demonstrate that the therapeutic index of NAMPT inhibitors may be increased in NAPRT1-deficient tumors by niacin supplementation.

Citation Format: Maria Quanz, Claudia Merz, Andreas Bernthaler, Stefan Kaulfuss, Anja Richter, Marcus Bauser, Andrea Haegebarth. Pharmacological characterization of a novel potent nicotinamide phosphoribosyltransferase (NAMPT) inhibitor with robust in vivo efficacy and increased therapeutic index with niacin supplementation. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1049.