TAK-1 Inhibitors & Cancer

Targeting Cancer Treatments Through Chemistry: Novel Small Molecule TAK-1 Inhibitors

With more than one million people in the United States diagnosed with cancer each year, the need for different treatment methods is more important now than ever. While drugs for cancer already exist, they often fail to be specific enough and thus cause harm to both cancer and normal cells. "Currently used chemotherapy often kills everything – both cancer and healthy cells," explains Justin Burns, licensing associate at Emory's Office of Technology Transfer. "Scientists now try to find and create compounds that take advantage of some property of cancer cells that distinguishes them from normal cells. The hope is that the cytotoxic compound binds or inhibits some action of cancer cells but not of normal healthy cells."

Huw Davies, PhD

Emory's Huw Davies, PhD, a fellow of the National Academy of Inventors (NAI), is a synthetic chemist who is currently working on this problem. Davies collaborates with biologists to create small novel compounds that inhibit certain proteins involved in normal body functions. Although these proteins are vital for proper cell function, if overexpressed, they may also lead to cancer.

Over the years, Davies has worked with such proteins, including aromatase, an enzyme involved in the production of estrogen. "The idea of this new aromatase inhibitor is to try to develop new analogues that can potentially have less off-target activity and a cleaner pharmacological profile," Davies says.

Collaborating with a structural biologist, who had already mapped the x-ray structure of the human aromatase enzyme, Davies was able to develop new analogues based off of the x-ray structure. "We developed some new chemistry that allowed ready access to a whole series of new analogues. In that series, we found some very potent compounds – more potent than some of the commercial drugs," says Davies.

Cancer Cells

Although further experimentation is necessary to confirm whether such compounds can be used as treatment methods, these analogues are certainly a promising start. With aromatase being overexpressed in more than 75% of breast cancer lines, creating inhibitors that are more specific can potentially reduce some of the adverse effects – such as bone and liver disease – that result from nonspecific binding.

Besides these aromatase inhibitors, Davies has also worked with the TAK-1 kinase to create anti-cancer agents. "This was a collaboration with a cancer geneticist who had hypothesized that TAK-1 would be a promising target for a new class of anti-cancer agents," says Davies. "He had done an extensive amount of genetic profiling with knock-out mice to validate this. To move his project forward, he would then need some TAK-1 inhibitors, which then could be evaluated as potential anti-cancer agents."

Techid: 10097 & 10098