Discovery of Novel Allosteric, Non-Bisphosphonate Inhibitors of Farnesyl Pyrophosphate Synthase by Integrated Lead Finding

Farnesyl pyrophosphate synthase (FPPS) is an established target for bone diseases, but also shows promise as an anticancer and anti-infective drug target. Currently available anti-FPPS drugs are active-site directed bisphosphonate inhibitors whose peculiar pharmacological profile is inadequate for therapeutic indications beyond bone diseases. The recent discovery of an allosteric binding site has paved the way towards the development of novel, non-bisphosphonate FPPS inhibitors with broader therapeutic potential, notably as immuno-modulators in oncology. Herein we report the discovery of two new classes of allosteric FPPS inhibitors by an integrated lead finding approach. We present their synthesis, biochemical and cellular activity, structure-activity relationships, and provide X-ray structures of several representative FPPS complexes