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Discovery of Novel Allosteric Non‐Bisphosphonate Inhibitors of Farnesyl Pyrophosphate Synthase by Integrated Lead Finding
Author(s) -
Marzinzik Andreas L.,
Amstutz René,
Bold Guido,
Bourgier Emmanuelle,
Cotesta Simona,
Glickman J. Fraser,
Götte Marjo,
Henry Christelle,
Lehmann Sylvie,
Hartwieg J. Constanze D.,
Ofner Silvio,
Pellé Xavier,
Roddy Thomas P.,
Rondeau JeanMichel,
Stauffer Frédéric,
Stout Steven J.,
Widmer Armin,
Zimmermann Johann,
Zoller Thomas,
Jahnke Wolfgang
Publication year - 2015
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201500338
Subject(s) - farnesyl pyrophosphate , allosteric regulation , bisphosphonate , drug discovery , chemistry , pharmacology , computational biology , biochemistry , biology , atp synthase , enzyme , osteoporosis , endocrinology
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.