Discovery of Novel Allosteric Non‐Bisphosphonate Inhibitors of Farnesyl Pyrophosphate Synthase by Integrated Lead Finding |
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Authors: | Dr. Andreas L. Marzinzik Dr. René Amstutz Dr. Guido Bold Emmanuelle Bourgier Dr. Simona Cotesta Dr. J. Fraser Glickman Dr. Marjo Götte Christelle Henry Sylvie Lehmann Dr. J. Constanze D. Hartwieg Dr. Silvio Ofner Xavier Pellé Dr. Thomas P. Roddy Dr. Jean‐Michel Rondeau Dr. Frédéric Stauffer Steven J. Stout Armin Widmer Dr. Johann Zimmermann Dr. Thomas Zoller Dr. Wolfgang Jahnke |
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Affiliation: | 1. Novartis Institutes for BioMedical Research, Basel, Switzerland;2. Conim AG, Zug, Switzerland;3. High Throughput and Spectroscopy Resource Center, Rockefeller University, New York, NY, USA;4. Agios, Cambridge, MA, USA;5. Merck Research Laboratories, Rahway, NJ, USA;6. Polyphor, Allschwil, Switzerland |
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Abstract: | Farnesyl pyrophosphate synthase (FPPS) is an established target for the treatment of 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, the peculiar pharmacological profile of which is inadequate for therapeutic indications beyond bone diseases. The recent discovery of an allosteric binding site has paved the way toward the development of novel non‐bisphosphonate FPPS inhibitors with broader therapeutic potential, notably as immunomodulators in oncology. Herein we report the discovery, by an integrated lead finding approach, of two new chemical classes of allosteric FPPS inhibitors that belong to the salicylic acid and quinoline chemotypes. We present their synthesis, biochemical and cellular activities, structure–activity relationships, and provide X‐ray structures of several representative FPPS complexes. These novel allosteric FPPS inhibitors are devoid of any affinity for bone mineral and could serve as leads to evaluate their potential in none‐bone diseases. |
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Keywords: | allosteric inhibitors antitumor agents anti-infective drug discovery FPPS immunomodulation immunotherapy |
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