title: Discovery of Novel Allosteric Non-Bisphosphonate Inhibitors of Farnesyl Pyrophosphate Synthase by Integrated Lead Finding.
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.
authors.affiliation: Novartis Institutes for BioMedical Research, Basel, 4002, Switzerland. wolfgang.jahnke@novartis.com.
authors.forename: Andreas L
authors.initials: AL
authors.lastname: Marzinzik
authors.affiliation: Novartis Institutes for BioMedical Research, Basel, 4002, Switzerland.|Conim AG, Oberwiler Kirchweg 4c, 6300, Zug, Switzerland.
authors.forename: René
authors.initials: R
authors.lastname: Amstutz
authors.affiliation: Novartis Institutes for BioMedical Research, Basel, 4002, Switzerland.
authors.forename: Guido
authors.initials: G
authors.lastname: Bold
authors.affiliation: Novartis Institutes for BioMedical Research, Basel, 4002, Switzerland.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Bourgier
authors.affiliation: Novartis Institutes for BioMedical Research, Basel, 4002, Switzerland.
authors.forename: Simona
authors.initials: S
authors.lastname: Cotesta
authors.affiliation: Novartis Institutes for BioMedical Research, Basel, 4002, Switzerland.|High Throughput and Spectroscopy Resource Center, Rockefeller University, New York, NY, 10065, USA.
authors.forename: J Fraser
authors.initials: JF
authors.lastname: Glickman
authors.affiliation: Novartis Institutes for BioMedical Research, Basel, 4002, Switzerland.
authors.forename: Marjo
authors.initials: M
authors.lastname: Götte
authors.affiliation: Novartis Institutes for BioMedical Research, Basel, 4002, Switzerland.
authors.forename: Christelle
authors.initials: C
authors.lastname: Henry
authors.affiliation: Novartis Institutes for BioMedical Research, Basel, 4002, Switzerland.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Lehmann
authors.affiliation: Novartis Institutes for BioMedical Research, Basel, 4002, Switzerland.
authors.forename: J Constanze D
authors.initials: JC
authors.lastname: Hartwieg
authors.affiliation: Novartis Institutes for BioMedical Research, Basel, 4002, Switzerland.
authors.forename: Silvio
authors.initials: S
authors.lastname: Ofner
authors.affiliation: Novartis Institutes for BioMedical Research, Basel, 4002, Switzerland.
authors.forename: Xavier
authors.initials: X
authors.lastname: Pellé
authors.affiliation: Novartis Institutes for BioMedical Research, Basel, 4002, Switzerland.|Agios, Cambridge, MA, 02139-4169, USA.
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Roddy
authors.affiliation: Novartis Institutes for BioMedical Research, Basel, 4002, Switzerland.
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Rondeau
authors.affiliation: Novartis Institutes for BioMedical Research, Basel, 4002, Switzerland.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Stauffer
authors.affiliation: Novartis Institutes for BioMedical Research, Basel, 4002, Switzerland.|Merck Research Laboratories, 126 E. Lincoln Avenue, Rahway, NJ, 07065, USA.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Stout
authors.affiliation: Novartis Institutes for BioMedical Research, Basel, 4002, Switzerland.
authors.forename: Armin
authors.initials: A
authors.lastname: Widmer
authors.affiliation: Novartis Institutes for BioMedical Research, Basel, 4002, Switzerland.|Polyphor, Hegenheimermattweg 125, 4123, Allschwil, Switzerland.
authors.forename: Johann
authors.initials: J
authors.lastname: Zimmermann
authors.affiliation: Novartis Institutes for BioMedical Research, Basel, 4002, Switzerland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Zoller
authors.affiliation: Novartis Institutes for BioMedical Research, Basel, 4002, Switzerland. andreas.marzinzik@novartis.com.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Jahnke
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D000495:Allosteric Site / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051228:Geranyltranstransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D015394:Molecular Structure; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D020156:Salicylic Acid / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D011804:Quinolines; C037219:quinoline; D051228:Geranyltranstransferase; D020156:Salicylic Acid
keywords: FPPS; allosteric inhibitors; anti-infective drug discovery; antitumor agents; immunomodulation; immunotherapy