New Drug Prevents Inhibition of the p53 Tumor Suppressor

Cancer researchers have designed a novel drug, MI-219, that is a potent, highly selective, and orally active small-molecule inhibitor of the interaction between the tumor suppressing protein p53 and its inhibitory protein MDM2 (murine double minute).

Investigators at the University of Michigan Comprehensive Cancer Center (Ann Arbor, USA) used a computer-assisted approach to design a small molecule that would bind to MDM2 and prevent it from interacting with p53. Their drug, MI-219, can be administered as an oral pill and has been found safe for use in animals.

Further details about MI-219 were published in the March 3, 2008, online edition of the Proceedings of the [U.S.] National Academy of Sciences (PNAS). MI-219 disrupted the MDM2–p53 interaction and activated the p53 pathway in cells with wild-type p53, which led to induction of cell cycle arrest in all cells and selective apoptosis in tumor cells. The drug stimulated rapid but transient p53 activation in established tumor xenograft tissues, resulting in inhibition of cell proliferation, induction of apoptosis, and complete tumor growth inhibition. MI-219 activated p53 in normal tissues with minimal p53 accumulation.

"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,” explained senior author Dr. Shaomeng Wang, professor of internal medicine and pharmacology at the University of Michigan Medical School. "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.”


Related Links:
University of Michigan Comprehensive Cancer Center