Crystallographic and thermodynamic characterization of phenylaminopyridine bisphosphonates binding to human farnesyl pyrophosphate synthase.

ABSTRACT: Human farnesyl pyrophosphate synthase (hFPPS) catalyzes the production of the 15-carbon isoprenoid farnesyl pyrophosphate. The enzyme is a key regulator of the mevalonate pathway and a well-established drug target. Notably, it was elucidated as the molecular target of nitrogen-containing bisphosphonates, a class of drugs that have been widely successful against bone resorption disorders. More recently, research has focused on the anticancer effects of these inhibitors. In order to achieve increased non-skeletal tissue exposure, we created phenylaminopyridine bisphosphonates (PNP-BPs) that have bulky hydrophobic side chains through a structure-based approach. Some of these compounds have proven to be more potent than the current clinical drugs in a number of antiproliferation assays using m

SUBMITTER: Park J 

PROVIDER: S-EPMC5643135 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature