Farnesyl Pyrophosphate Synthase as a Target for Drug Development: Discovery of Natural-Product-Derived Inhibitors and Their Activity in Pancreatic Cancer Cells

Human farnesyl pyrophosphate synthase (Homo sapiens FPPS, HsFPPS) is a target for treating bone resorption
diseases and some cancers. HsFPPS is potently inhibited
by bisphosphonates, but due to poor cell penetration and distribution
in soft tissue, there is currently interest in the development of
non-bisphosphonate inhibitors as cancer therapeutics. Here, we report
the discovery and development of HsFPPS inhibitors
based on the phenolic diterpene carnosic acid (CA), an
antimicrobial found in rosemary and sage, which showed better cellular
anticancer activities than the bisphosphonate drug zoledronate in
pancreatic cancer cell lines, as well as an HsFPPS-dependent
mechanism of action. Hit-to-lead optimization of CA improved HsFPPS inhibition by >100-fold. A slow dissociation inhibition
pattern and a noncompetitive allosteric binding mode were found, and
cellular mechanism-of-action studies showed that these inhibitors
inhibit tumor cell growth primarily by inhibiting HsFPPS, leading to downregulation of Ras prenylation and cell apoptosis.
The discovery of this series of compounds together with proof-of-mechanism
in pancreatic cancer cells may pave the way for targeting HsFPPS in soft tissue cancers using natural-product-derived
inhibitors.