Allosteric non-bisphosphonate FPPS inhibitors identified by fragment-based discovery

Wolfgang Jahnke; Jean-Michel Rondeau; Simona Cotesta; Andreas Marzinzik; Xavier Pellé; Martin Geiser; André Strauss; Marjo Götte; Francis Bitsch; René Hemmig; Chrystèle Henry; Sylvie Lehmann; J Fraser Glickman; Thomas P Roddy; Steven J Stout; Jonathan R Green

doi:10.1038/nchembio.421

Allosteric non-bisphosphonate FPPS inhibitors identified by fragment-based discovery

Nat Chem Biol. 2010 Sep;6(9):660-6. doi: 10.1038/nchembio.421. Epub 2010 Aug 15.

Authors

Wolfgang Jahnke¹, Jean-Michel Rondeau, Simona Cotesta, Andreas Marzinzik, Xavier Pellé, Martin Geiser, André Strauss, Marjo Götte, Francis Bitsch, René Hemmig, Chrystèle Henry, Sylvie Lehmann, J Fraser Glickman, Thomas P Roddy, Steven J Stout, Jonathan R Green

Affiliation

¹ Center for Proteomic Chemistry and Global Discovery Chemistry, Novartis Institutes for Biomedical Research, Basel, Switzerland. wolfgang.jahnke@novartis.com

PMID: 20711197
DOI: 10.1038/nchembio.421

Abstract

Bisphosphonates are potent inhibitors of farnesyl pyrophosphate synthase (FPPS) and are highly efficacious in the treatment of bone diseases such as osteoporosis, Paget's disease and tumor-induced osteolysis. In addition, the potential for direct antitumor effects has been postulated on the basis of in vitro and in vivo studies and has recently been demonstrated clinically in early breast cancer patients treated with the potent bisphosphonate zoledronic acid. However, the high affinity of bisphosphonates for bone mineral seems suboptimal for the direct treatment of soft-tissue tumors. Here we report the discovery of the first potent non-bisphosphonate FPPS inhibitors. These new inhibitors bind to a previously unknown allosteric site on FPPS, which was identified by fragment-based approaches using NMR and X-ray crystallography. This allosteric and druggable pocket allows the development of a new generation of FPPS inhibitors that are optimized for direct antitumor effects in soft tissue.

MeSH terms

Allosteric Regulation
Allosteric Site
Bone and Bones / chemistry
Bone and Bones / metabolism
Crystallography, X-Ray
Diphosphonates* / analysis
Diphosphonates* / chemistry
Diphosphonates* / metabolism
Diphosphonates* / pharmacology
Drug Evaluation, Preclinical*
Enzyme Inhibitors / analysis*
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Geranyltranstransferase / antagonists & inhibitors*
Geranyltranstransferase / metabolism
Humans
Imidazoles / analysis
Imidazoles / chemistry
Imidazoles / pharmacology
Magnetic Resonance Spectroscopy
Soft Tissue Neoplasms / drug therapy
Zoledronic Acid

Substances

Diphosphonates
Enzyme Inhibitors
Imidazoles
Zoledronic Acid
Geranyltranstransferase

Associated data

PDB/3N1V
PDB/3N1W
PDB/3N3L
PDB/3N45
PDB/3N46
PDB/3N49
PDB/3N5H
PDB/3N5J
PDB/3N6K
PubChem-Substance/97857842
PubChem-Substance/97857843
PubChem-Substance/97857844
PubChem-Substance/97857845
PubChem-Substance/97857846
PubChem-Substance/97857847
PubChem-Substance/97857848
PubChem-Substance/97857849
PubChem-Substance/97857850
PubChem-Substance/97857851
PubChem-Substance/97857852
PubChem-Substance/97857853