Multistage screening reveals chameleon ligands of the human farnesyl pyrophosphate synthase: implications to drug discovery for neurodegenerative diseases

J Med Chem. 2014 Jul 10;57(13):5764-76. doi: 10.1021/jm500629e. Epub 2014 Jun 23.


Human farnesyl pyrophosphate synthase (hFPPS) is the gate-keeper of mammalian isoprenoids and the key target of bisphosphonate drugs. Bisphosphonates suffer from poor "drug-like" properties and are mainly effective in treating skeletal diseases. Recent investigations have implicated hFPPS in various nonskeletal diseases, including Alzheimer's disease (AD). Analysis of single nucleotide polymorphisms in the hFPPS gene and mRNA levels in autopsy-confirmed AD subjects was undertaken, and a genetic link between hFPPS and phosphorylated tau (P-Tau) levels in the human brain was identified. Elevated P-Tau levels are strongly implicated in AD progression. The development of nonbisphosphonate inhibitors can provide molecular tools for validating hFPPS as a therapeutic target for tauopathy-associated neurodegeneration. A multistage screening protocol led to the identification of a new monophosphonate chemotype that bind in an allosteric pocket of hFPPS. Optimization of these compounds could lead to human therapeutics that block tau metabolism and arrest the progression of neurodegeneration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Site / drug effects
  • Alzheimer Disease / genetics
  • Alzheimer Disease / physiopathology
  • Catalytic Domain
  • Crystallography, X-Ray
  • Diphosphonates / pharmacology
  • Drug Evaluation, Preclinical
  • Enzyme Inhibitors / pharmacology*
  • Geranyltranstransferase / antagonists & inhibitors*
  • Geranyltranstransferase / genetics
  • Geranyltranstransferase / metabolism
  • Humans
  • Ligands
  • Neurodegenerative Diseases / drug therapy
  • Organophosphonates / chemical synthesis
  • Organophosphonates / pharmacology*
  • Phosphorylation
  • Polymorphism, Single Nucleotide
  • Pyrimidines / pharmacology
  • tau Proteins / metabolism


  • Diphosphonates
  • Enzyme Inhibitors
  • Ligands
  • Organophosphonates
  • Pyrimidines
  • tau Proteins
  • thienopyrimidine
  • Geranyltranstransferase