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Discovery of Novel Allosteric, Non-Bisphosphonate Inhibitors of Farnesyl Pyrophosphate Synthase by Integrated Lead Finding

Marzinzik, Andreas and Amstutz, Rene and Bold, Guido and Bourgier, Emmanuelle and Cotesta, Simona and Glickman, Fraser and Goette, Marjo and Henry, Christelle and Lehmann, Sylvie and Hartwieg, Constanze and Ofner, Silvio and Pelle, Xavier and Roddy, Thomas and Rondeau, Jean-Michel and Stauffer, Frederic and Stout, Steven and Widmer, Armin and Zimmermann, Johann and Zoller, Thomas and Jahnke, Wolfgang (2015) Discovery of Novel Allosteric, Non-Bisphosphonate Inhibitors of Farnesyl Pyrophosphate Synthase by Integrated Lead Finding. ChemMedChem, 10 (11). pp. 1884-1891. ISSN 18607179

Abstract

Farnesyl pyrophosphate synthase (FPPS) is an established target for bone diseases, but also shows promise as an anticancer and anti-infective drug target. Currently available anti-FPPS drugs are active-site directed bisphosphonate inhibitors whose peculiar pharmacological profile is inadequate for therapeutic indications beyond bone diseases. The recent discovery of an allosteric binding site has paved the way towards the development of novel, non-bisphosphonate FPPS inhibitors with broader therapeutic potential, notably as immuno-modulators in oncology. Herein we report the discovery of two new classes of allosteric FPPS inhibitors by an integrated lead finding approach. We present their synthesis, biochemical and cellular activity, structure-activity relationships, and provide X-ray structures of several representative FPPS complexes.

Item Type: Article
Date Deposited: 12 May 2016 23:45
Last Modified: 12 May 2016 23:45
URI: https://oak.novartis.com/id/eprint/26609

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