NAMPT, an enzyme essential for NAD þ biosynthesis, has been extensively studied as an anticancer target for developing potential novel therapeutics. Several NAMPT inhibitors have been discovered, some of which have been subjected to clinical investigations. Yet, the on-target hematological and retinal toxicities have hampered their clinical development. In this study, we report the discovery of a unique NAMPT inhibitor, LSN3154567. This molecule is highly selective and has a potent and broad spectrum of anticancer activity. Its inhibitory activity can be rescued with nicotinic acid (NA) against the cell lines proficient, but not those deficient in NAPRT1, essential for converting NA to NAD þ

<div>Abstract<p>NAMPT, an enzyme essential for NAD⁺ biosynthesis, has been extensively studied as an anticancer target for developing potential novel therapeutics. Several NAMPT inhibitors have been discovered, some of which have been subjected to clinical investigations. Yet, the on-target hematological and retinal toxicities have hampered their clinical development. In this study, we report the discovery of a unique NAMPT inhibitor, LSN3154567. This molecule is highly selective and has a potent and broad spectrum of anticancer activity. Its inhibitory activity can be rescued with nicotinic acid (NA) against the cell lines proficient, but not those deficient in NAPRT1, essential for converting NA to NAD⁺. LSN3154567 also exhibits robust efficacy in multiple tumor models deficient in NAPRT1. Importantly, this molecule when coadministered with NA does not cause observable retinal and hematological toxicities in the rodents, yet still retains robust efficacy. Thus, LSN3154567 has the potential to be further developed clinically into a novel cancer therapeutic. <i>Mol Cancer Ther; 16(12); 2677–88. ©2017 AACR</i>.</p></div>

<p>Table S1: anti-proliferative activity of LSN3154567 against different cancer cell lines; Table S2: effects of NAM on the anti-proliferative activity of LSN3154567</p>

<p>The concentrations of LSN3154567 in the dog plasma samples.</p>

<p>Addition of NAM rescued the inhibitory activity of LSN3154567</p>

<p>A and B, NCI-H1155 and HCT116 cells were grown and treated in duplicates with LSN3154567 (100 nM), respectively, as described (Materials and Methods) and apoptosis was analyzed as described above.</p>

<div>Abstract<p>NAMPT, an enzyme essential for NAD⁺ biosynthesis, has been extensively studied as an anticancer target for developing potential novel therapeutics. Several NAMPT inhibitors have been discovered, some of which have been subjected to clinical investigations. Yet, the on-target hematological and retinal toxicities have hampered their clinical development. In this study, we report the discovery of a unique NAMPT inhibitor, LSN3154567. This molecule is highly selective and has a potent and broad spectrum of anticancer activity. Its inhibitory activity can be rescued with nicotinic acid (NA) against the cell lines proficient, but not those deficient in NAPRT1, essential for converting NA to NAD⁺. LSN3154567 also exhibits robust efficacy in multiple tumor models deficient in NAPRT1. Importantly, this molecule when coadministered with NA does not cause observable retinal and hematological toxicities in the rodents, yet still retains robust efficacy. Thus, LSN3154567 has the potential to be further developed clinically into a novel cancer therapeutic. <i>Mol Cancer Ther; 16(12); 2677–88. ©2017 AACR</i>.</p></div>

<p>Table S1: anti-proliferative activity of LSN3154567 against different cancer cell lines; Table S2: effects of NAM on the anti-proliferative activity of LSN3154567</p>