Better Bisphosphonates

New lipophilic bisphosphonate compounds that act on multiple enzymes could lead to improved anticancer drugs as well as treatments for tropical diseases.

Although bisphosphonate drugs were originally developed for osteoporosis and other bone diseases, recent clinical trials have demonstrated that they also have anticancer activity and immune-enhancing benefits. But current bisphosphonates may not be optimal against soft-tissue tumors because they bind strongly to bone.

Now, an international team of 24 researchers led by chemistry professor Eric Oldfield of the University of Illinois, Urbana-Champaign, reports a lipophilic bisphosphonate called BPH-715 that is up to 200 times better at killing tumor cells and more bioavailable to soft-tissue tumors than traditional bisphosphonates (J. Amer. Chem. Soc., DOI: 10.1021/ja808285e).

"Our compounds are tagged with a lipophilic tail so they bind less strongly to bone and more readily cross cell membranes," making them more effective than current bisphosphonates at killing soft-tissue tumors in mice, Oldfield says. These new compounds also kick-start the production of 100 times more cancer-killing immune system ??T cells than current bisphosphonates, he adds.

"Such lipophilic bisphosphonates may be suitable lead structures, or ideally preclinical candidates, in the search for novel anticancer agents," says Wolfgang Jahnke, who studies bisphosphonate biology and chemistry at the Novartis Institutes of Biomedical Research, in Basel, Switzerland. Novartis makes zoledronate, a traditional bisphosphonate drug for treating excessive bone resorption.

Bisphosphonates in clinical-use target an enzyme called farnesyl diphosphate synthase (FPPS). Inhibiting it impairs cancer cell-survival signaling pathways that involve synthesizing isoprenoids. Oldfield and coworkers engineered the lipophilic compounds to inhibit both FPPS and a similar enzyme called geranylgeranyl diphosphate synthase (GGPPS), which recent work has indicated may also be a viable target for anticancer drugs. Crystallographic studies demonstrate that BPH-715 binds FPPS but primarily inhibits GGPPS.

Roberto Docampo, a biochemist at the University of Georgia, praises the "elegant structural and chemical studies." He adds that lipophilic bisphosphonates may also be useful in developing drugs to treat African sleeping sickness and malaria, both of which have cell-signaling pathways that involve FPPS and GGPPS.