Lipophilic Bisphosphonates as Dual Farnesyl/Geranylgeranyl Diphosphate Synthase Inhibitors: An X-ray and NMR Investigation
Yonghui Zhang†, Rong Cao‡, Fenglin Yin‡, Michael P. Hudock‡, Rey-Ting Guo§, Kilannin Krysiak†, Sujoy Mukherjee‡, Yi-Gui Gao†, Howard Robinson, Yongcheng Song†, Joo Hwan No‡, Kyle Bergan†, Annette Leon‡, Lauren Cass†, Amanda Goddard†, Ting-Kai Chang†, Fu-Yang Lin‡, Ermond Van Beek, Socrates Papapoulos, Andrew H.-J. Wang§, Tadahiko Kubo#, Mitsuo Ochi#, Dushyant Mukkamala‡ and Eric Oldfield†‡
Considerable effort has focused on the development of selective protein farnesyl transferase (FTase) and protein geranylgeranyl transferase (GGTase) inhibitors as cancer chemotherapeutics. Here, we report a new strategy for anticancer therapeutic agents involving inhibition of farnesyl diphosphate synthase (FPPS) and geranylgeranyl diphosphate synthase (GGPPS), the two enzymes upstream of FTase and GGTase, by lipophilic bisphosphonates. Due to dual site targeting and decreased polarity, the compounds have activities far greater than do current bisphosphonate drugs in inhibiting tumor cell growth and invasiveness, both in vitro and in vivo. We explore how these compounds inhibit cell growth and how cell activity can be predicted based on enzyme inhibition data, and using X-ray diffraction, solid state NMR, and isothermal titration calorimetry, we show how these compounds bind to FPPS and/or GGPPS.