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

TitleMultistage screening reveals chameleon ligands of the human farnesyl pyrophosphate synthase: implications to drug discovery for neurodegenerative diseases.
Publication TypeJournal Article
Year of Publication2014
AuthorsDe Schutter JW, Park J, Leung CYuen, Gormley P, Lin Y-S, Hu Z, Berghuis AM, Poirier J, Tsantrizos YS
JournalJ Med Chem
Volume57
Issue13
Pagination5764-76
Date Published2014 Jul 10
ISSN1520-4804
KeywordsAllosteric Site, Alzheimer Disease, Catalytic Domain, Crystallography, X-Ray, Diphosphonates, Drug Evaluation, Preclinical, Enzyme Inhibitors, Geranyltranstransferase, Humans, Ligands, Neurodegenerative Diseases, Organophosphonates, Phosphorylation, Polymorphism, Single Nucleotide, Pyrimidines, tau Proteins
Abstract

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.

DOI10.1021/jm500629e
Alternate JournalJ. Med. Chem.
PubMed ID24911527
Grant List / / Canadian Institutes of Health Research / Canada

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