A team of 24 researchers from the U.S., Europe, Taiwan and Japan and led by University of Illinois scientists has engineered a new anti-cancer agent that is about 200 times more active in killing tumor cells than similar drugs used in recent clinical trials. The study appears in the April issue of the Journal of the American Chemical Society.

The new agent belongs to a class of drugs called bisphosphonates. These compounds were originally developed to treat osteoporosis and other bone diseases, but were recently found to also have potent anti-cancer and immune boosting properties.

Nearly a third of human cancers involve a mutation in the Ras gene that causes cell signaling to go awry. Bisphosphonates act on other enzymes called FPPS and GGPPS, which are upstream of Ras in the cell survival pathway. Inhibiting these enzymes appears to be a more effective strategy for killing cancer cells.

When used in combination with hormone therapy in a recent clinical trial, the bisphosphonates drug Zoledronate significantly reduced the recurrence of breast cancer in premenopausal women with estrogen-receptor-positive breast cancer. Similar results were reported previously for hormone-refractory prostate cancer.

But as Zoledronate quickly binds to bone, reducing its efficacy in other tissues, the aim was to develop bisphosphonates that wil be very active but won't bind to the bone.

The researchers 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 bisphosphonates 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. In humans, they 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.

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