Work

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

Year: 2019

Type: article

Abstract: Human farnesyl pyrophosphate synthase ( Homo sapiens FPPS, Hs FPPS) is a target for treating bone resorption diseases and some cancers. Hs 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 Hs FPPS 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 Hs FPPS-dependent mechanism of action. Hit-to-lead optimization of CA improved Hs 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 Hs 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 Hs FPPS in soft tissue cancers using natural-product-derived inhibitors.

Source: Journal of Medicinal Chemistry

DOI: 10.1021/acs.jmedchem.9b01405