Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 56, Issue 20, Pages 7939-7950Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm400946f
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Funding
- Natural Sciences and Engineering Research Council of Canada (NSERC)
- Canada Foundation for Innovation (CFI)
- Quebec Ministere de la Recherche en Science et Technologie (FQRNT)
- McGill University
- NSERC
- FQRNT
- Canadian Institute of Health Research (CIHR)
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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.
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