U-M researchers ID promising new cancer drug

Small-molecule drug selectively kills tumor cells by activating p53 protein

ANN ARBOR, Mich. — Researchers have long searched for a novel cancer drug that activates a certain protein to kill tumor cells. But finding a drug that kills the cancer without causing damage to normal cells has stymied researchers.
MI-219 binds to MDM2 to prevent MDM2 from inhibiting p53
MI-219 binds to MDM2 to prevent MDM2 from inhibiting p53

Now, researchers at the University of Michigan Comprehensive Cancer Center have designed a small molecule that is highly effective in cell cultures at inhibiting the interaction between this protein, called p53, and another protein that inactivates p53 in cancer. The new molecule is ideal for drug development as it can be given orally as a pill and it appears to be safe for use in animals.

“For more than 10 years scientists have searched for ways to block p53 inhibition, but with little success. Our study clearly shows that this can be done,” says study author Shaomeng Wang, Ph.D., Warner-Lambert/Parke-Davis Professor in Medicine at the U-M Medical School and co-director of the molecular therapeutics program at the U-M Comprehensive Cancer Center.

If clinical trials prove out the drug’s promise, it could have potential for treating many different types of cancer. Results of the study appear the week of March 3 in the online edition of the Proceedings of the National Academy of Sciences.

The protein p53, which normally helps suppress tumors, is inactivated in almost all human cancers. About half the time, p53 does not do its job because the gene that holds the protein is mutated or missing altogether. The other half of the time, another protein, called human MDM2, is the culprit. It binds to p53 and inhibits the tumor suppressor function of p53, promoting cancer development.

Using a computer-assisted approach, U-M researchers designed a small molecule, called MI-219, that is highly effective in blocking the interaction of MDM2 and p53. MI-219 specifically kills tumor cells by harnessing the power of p53. In animal models of human cancer, MI-219 completely inhibited tumor growth and appeared to cause no toxicity to animals.

Dr. Wang“Many traditional cancer drugs also activate p53 but they do so by causing DNA damage. They kill not only tumor cells but also normal cells, thus having severe side effects. MI-219 is unique in that it is designed to activate p53 without causing DNA damage, specifically killing tumor cells. Indeed, MI-219 is highly effective in inhibiting tumor growth, and even inducing tumor regression, but it has caused no toxicity to animals at efficacious doses,” says Wang, professor of internal medicine and pharmacology at the U-M Medical School and professor of medicinal chemistry at the U-M College of Pharmacy.

In addition to its effectiveness at killing cancer cells without toxic side effects, MI-219 can be developed as a pill that patients could take orally, rather than the traditional chemotherapy drugs that must be given intravenously at a hospital or cancer center.

“While promising in preclinical studies, MI-219 needs to be evaluated in human clinical trials for its safety and efficacy for cancer treatment since it is a brand new drug,” Wang cautions.

“We are very excited about the therapeutic potential of MI-219 for the treatment of many types of human cancer. Ascenta is committed to advancing MI-219, which we have designated AT-219, into human clinical trials,” says study author Dajun Yang, M.D., Ph.D., senior vice president of research and a co-founder of Ascenta Therapeutics, a clinical-stage biopharmaceutical company that has licensed the technology related to MI-219 from U-M and plans to aggressively advance it into human clinical trials.

MI-219 is in preclinical studies and not yet ready for human trials in cancer patients. For questions about currently available cancer treatments, call the U-M Cancer AnswerLine at 800-865-1125 or visit www.mcancer.org.

The lead author on the study was Sanjeev Shangary, Ph.D., research investigator at the U-M Medical School. Other authors were Dongguang Qin, Donna McEachern, Meilan Liu, Rebecca Miller, Su Qiu, Zaneta Nikolovska-Coleska, Ke Ding, Guoping Wang, Jianyong Chen, Denzil Bernard, Jian Zhang, Yipin Lu, Qingyang Gu, Rajal Shah, Kenneth Pienta and Yi Sun, all from the University of Michigan; and Xiaolan Ling, Sanmao Kang, Ming Guo, and Dajun Yang from Ascenta Therapeutics Inc.

Funding for the study is from the National Cancer Institute, a U-M Prostate Cancer SPORE grant, the Leukemia and Lymphoma Society, the Prostate Cancer Foundation, Ascenta Therapeutics Inc. and the U-M Comprehensive Cancer Center.

The University of Michigan has filed a patent application for MI-219 and its related molecules. The technology has been licensed by Ascenta. U-M and Wang have equity in Ascenta. Wang is a scientific founder of Ascenta and serves as its chief scientific adviser and is the principal investigator on a research contract from Ascenta to U-M.

Reference: Proceedings of the NationalAcademy of Sciences, published online week of March 3, 2008

Written by: Nicole Fawcett