Pharmacophore Mapping of Thienopyrimidine-Based Monophosphonate (ThP-MP) Inhibitors of the Human Farnesyl Pyrophosphate Synthase

The
human farnesyl pyrophosphate synthase (hFPPS), a key regulatory
enzyme in the mevalonate pathway, catalyzes the biosynthesis of the
C-15 isoprenoid farnesyl pyrophosphate (FPP). FPP plays a crucial
role in the post-translational prenylation of small GTPases that perform
a plethora of cellular functions. Although hFPPS is a well-established
therapeutic target for lytic bone diseases, the currently available
bisphosphonate drugs exhibit poor cellular uptake and distribution
into nonskeletal tissues. Recent drug discovery efforts have focused
primarily on allosteric inhibition of hFPPS and the discovery of non-bisphosphonate
drugs for potentially treating nonskeletal diseases. Hit-to-lead optimization
of a new series of thienopyrimidine-based monosphosphonates (ThP-MPs)
led to the identification of analogs with nanomolar potency in inhibiting
hFPPS. Their interactions with the allosteric pocket of the enzyme
were characterized by crystallography, and the results provide further
insight into the pharmacophore requirements for allosteric inhibition.