Thienopyrimidine Bisphosphonate (ThPBP) Inhibitors of the Human Farnesyl Pyrophosphate Synthase: Optimization and Characterization of the Mode of Inhibition

J Med Chem. 2013 Oct 24;56(20):7939-50. doi: 10.1021/jm400946f. Epub 2013 Oct 3.

Abstract

Human farnesyl pyrophosphate synthase (hFPPS) controls the post-translational prenylation of small GTPase proteins that are essential for cell signaling, cell proliferation, and osteoclast-mediated bone resorption. Inhibition of hFPPS is a clinically validated mechanism for the treatment of lytic bone diseases, including osteoporosis and cancer related bone metastases. A new series of thienopyrimidine-based bisphosphonates (ThP-BPs) were identified that inhibit hFPPS with low nanomolar potency. Crystallographic evidence revealed binding of ThP-BP inhibitors in the allylic subpocket of hFPPS. Simultaneous binding of inorganic pyrophosphate in the IPP subpocket leads to conformational closing of the active site cavity. The ThP-BP analogues are significantly less hydrophilic yet exhibit higher affinity for the bone mineral hydroxyapatite than the current N-BP drug risedronic acid. The antiproliferation properties of a potent ThB-BP analogue was assessed in a multiple myeloma cell line and found to be equipotent to the best current N-BP drugs. Consequently, these compounds represent a new structural class of hFPPS inhibitors and a novel scaffold for the development of human therapeutics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Catalytic Domain
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Crystallography, X-Ray
  • Diphosphates / chemistry
  • Diphosphates / metabolism
  • Diphosphonates / chemistry
  • Diphosphonates / pharmacology*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Geranyltranstransferase / antagonists & inhibitors*
  • Geranyltranstransferase / chemistry
  • Geranyltranstransferase / metabolism
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Protein Binding
  • Protein Conformation
  • Protein Structure, Tertiary
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology*

Substances

  • Diphosphates
  • Diphosphonates
  • Enzyme Inhibitors
  • Pyrimidines
  • thienopyrimidine
  • Geranyltranstransferase