Taxodione and arenarone inhibit farnesyl diphosphate synthase by binding to the isopentenyl diphosphate site

There is an ever-present need for new drugs because of drug resistance. An enzyme called “farnesyl diphosphate synthase” (FPPS) is one important drug target, and drugs called “bisphosphonates” that inhibit this enzyme are of interest both as cancer therapeutics and as antibacterial and antiparasitic drug leads. However, they bind avidly to bone and so are ineffective against most tumors and most infectious organisms. Here, we report the discovery of compounds that lack a bone-binding feature that target FPPS in a unique way, as observed at the atomic level. They also can bind to other protein targets, providing a potentially important approach, multitarget inhibition, that is expected to increase efficacy and decrease the likelihood that resistance will develop.