Structure based design of nicotinamide phosphoribosyltransferase (NAMPT) inhibitors from a phenotypic screen. Issue 3 (1st February 2018)

• Record Type: Journal Article
• Authors: Palacios, Daniel S.; Meredith, Erik; Kawanami, Toshio; Adams, Christopher; Chen, Xin; Darsigny, Veronique; Geno, Erin; Palermo, Mark; Baird, Daniel; Boynton, Geoffrey; Busby, Scott A.; George, Elizabeth L.; Guy, Chantale; Hewett, Jeffrey; Tierney, Laryssa; Thigale, Sachin; Weihofen, Wilhelm; Wang, Louis; White, Nicole; Yin, Ming; Argikar, Upendra A.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 28:Issue 3(2018)
• Page Start: 365
• Page End: 370
• Publication Date: 2018-02-01
• Subjects: NAMPT -- In silico screen -- Structure based drug design -- Cyclopropane -- Nicotinamide phosphoribosyltransferase; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2017.12.037
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: Nicotinamide phosphoribosyltransferase is a key metabolic enzyme that is a potential target for oncology. Utilizing publicly available crystal structures of NAMPT and in silico docking of our internal compound library, a NAMPT inhibitor, 1, obtained from a phenotypic screening effort was replaced with a more synthetically tractable scaffold. This compound then provided an excellent foundation for further optimization using crystallography driven structure based drug design. From this approach, two key motifs were identified, the ( S, S ) cyclopropyl carboxamide and the ( S )-1- N -phenylethylamide that endowed compounds with excellent cell based potency. As exemplified by compound 27e such compounds could be useful tools to explore NAMPT biology in vivo .