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

Abstract

Human farnesyl pyrophosphate synthase (<i>Homo sapiens</i> FPPS, <i>Hs</i>FPPS) is a target for treating bone resorption diseases and some cancers. <i>Hs</i>FPPS 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 <i>Hs</i>FPPS inhibitors based on the phenolic diterpene carnosic acid (<b>CA</b>), 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 <i>Hs</i>FPPS-dependent mechanism of action. Hit-to-lead optimization of <b>CA</b> improved <i>Hs</i>FPPS 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 <i>Hs</i>FPPS, 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 <i>Hs</i>FPPS in soft tissue cancers using natural-product-derived inhibitors.