15357163mct160674-sup-173057_4_supp_4272916_9wc4z9.pptx (159.07 kB)
Figure S6 from Discovery of a Highly Selective NAMPT Inhibitor That Demonstrates Robust Efficacy and Improved Retinal Toxicity with Nicotinic Acid Coadministration
figureposted on 2023-04-03, 16:06 authored by Genshi Zhao, Colin F. Green, Yu-Hua Hui, Lourdes Prieto, Robert Shepard, Sucai Dong, Tao Wang, Bo Tan, Xueqian Gong, Lisa Kays, Robert L. Johnson, Wenjuan Wu, Shobha Bhattachar, Miriam Del Prado, James R. Gillig, Maria-Carmen Fernandez, Ken D. Roth, Sean Buchanan, Ming-Shang Kuo, Sandaruwan Geeganage, Timothy P. Burkholder
Association of NAPRT1 expression level with sensitivity of cancer cells to NAMPT inhibition by LSN3154567 in the presence of NA
Eli Lilly and Company
ARTICLE ABSTRACTNAMPT, 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. Mol Cancer Ther; 16(12); 2677–88. ©2017 AACR.
Drug Discovery TechnologiesScreening strategies (assays and chemical libraries)Drug TargetsGastrointestinal CancersColorectal cancerStomach cancerGynecological CancersEndometrial cancerOvarian cancerHematological CancersLeukemiasPharmacologyMolecular pharmacologyPharmacokinetics and pharmacodynamics