Structure based design of nicotinamide phosphoribosyltransferase (NAMPT) inhibitors from a phenotypic screen |
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| Authors: | Daniel S Palacios Erik Meredith Toshio Kawanami Christopher Adams Xin Chen Veronique Darsigny Erin Geno Mark Palermo Daniel Baird Geoffrey Boynton Scott A Busby Elizabeth L George Chantale Guy Jeffrey Hewett Laryssa Tierney Sachin Thigale Wilhelm Weihofen Louis Wang Upendra A Argikar |
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| Institution: | 1. Global Discovery Chemistry, Novartis Institute for Biomedical Research, 22 Windsor Street, Cambridge, MA 02139, USA;2. Chemical Biology and Therapeutics, Novartis Institute for Biomedical Research, 181 Massachusetts Avenue, Cambridge, MA 02139, USA;3. PK Sciences, Novartis Institute for Biomedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA |
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| 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. |
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| Keywords: | NAMPT Structure based drug design Cyclopropane Nicotinamide phosphoribosyltransferase |
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