Andrew Wang, of Academia Sinica, Taipei, and Illinois chemist Rong Cao began by producing crystallographic structures of the target enzymes and drug candidates, allowing the researchers to identify those features that would enhance the drugs' ability to bind to the enzymes. Using this and other chemical data, Illinois chemistry department research scientist Yonghui Zhang engineered new bisphosphonate compounds that bound tightly to multiple enzyme targets, but not to bone.
One of the new compounds, called BPH-715, proved to be especially potent in cell culture and effectively inhibited tumor cell growth and invasiveness.
Tadahiko Kubo, of Hiroshima University, then found that BPH-715 also killed tumor cells in mice. And Socrates Papapoulos, of Leiden University, the Netherlands, showed that the compound had a very low chemical affinity for bone.
In humans, compounds like BPH-715 and zoledronate have an added benefit in fighting cancer: They spur the proliferation of immune cells called gamma delta T-cells, which aid in killing tumor cells.
"The new drugs are about 200 times more effective than the drugs used in recent clinical trials at killing tumor cells and in activating gamma delta T-cells to kill tumor cells," Oldfield said. "They also prevent tumor progression in mice much better than do existing bisphosphonate molecules."
|Contact: Diana Yates|
University of Illinois at Urbana-Champaign