A study led by researchers at the University of Michigan Comprehensive Cancer Center showed in animal studies that new cancer drug compounds they developed shrank tumors, with few side effects. The study, done in two mouse models of human cancer, looked at two compounds designed to activate a protein that kills cancer cells. The protein, p53, is inactivated in a significant number of human cancers. In some cases, it is because another protein, MDM2, binds to p53 and blocks its tumor suppressor function. This allows the tumor to grow unchecked. The new compounds block MDM2 from binding to p53, consequently activating p53.

?For the first time, we showed that activation of p53 by our highly potent and optimized MDM2 inhibitors can achieve complete tumor regression in a mouse model of human cancer,? says lead study author Shaomeng Wang, Ph.D., Warner-Lambert/Parke-Davis Professor in Medicine and director of the Cancer Drug Discovery Program at the University of Michigan Comprehensive Cancer Center.

Wang presented the study at the American Association for Cancer Research 102nd annual meeting.

Many traditional cancer drugs also activate p53 but they do so by causing DNA damage in both tumor cells and normal cells, causing side effects. These new MDM2 inhibitors activate p53 while avoiding the DNA damage common with other drugs. In this study, which was done in collaboration with Ascenta Therapeutics and Sanonfi-Aventis, researchers showed that these new drugs shrank tumors without significant side effects.

Because p53 is involved in all types of human cancer, the new drug has potential to be used in multiple types of cancer. Further, the researchers also identified certain markers in tumors that predict which ones will be particularly sensitive to the MDM2 inhibitor, which would allow physicians to target the drug only to patients most likely to benefit.

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Blocking the interaction of MDM2-p53
Although genetic activation of p53 has been shown to achieve complete tumor eradication in mice, the best small-molecule inhibitors of the MDM2-p53 interaction reported to date (Nutlins including RG7112 or first generation spiro-oxindoles such as AT219) can only inhibit tumor growth but fail to achieve significant tumor regression in animal models of human cancer.

In this study, researchers demonstrated, for the first time, that 2 highly optimized spiro-oxindole compounds, are capable of achieving complete tumor regression or even permanent cure in multiple xenograft models of human cancer (sarcoma, leukemia, prostate) without causing any significant signs of toxicity to animals. The optimized spiro-oxindole compounds bind to human MDM2 protein with Ki values of <1 nM, 5000-times more potent than the wild-type p53 peptide. These potent MDM2 inhibitors are capable of activating p53 at concentrations as low as 30-100 nM and induce robust p53-dependent cell cycle arrest and apoptosis against tumor cells with wild-type p53.

Both compounds display good pharmacokinetic and pharmacodynamic profiles in animals. For instance, clearance is low in mice and moderate in dog representing 4 and 30 % of hepatic blood flow respectively. Importantly, excellent oral bioavailability was shown with >50 % F in dogs and 75 % F in mice and both compounds trigger rapid and sustained activation of pharmacodynamic biomarkers such as p53, p21, MDM2 and PUMA. Molecular profiling using large number of primary AML leukemia samples have identified that AML cells with wild-type p53 and FLT3-ITD mutation are exquisitely sensitive to apoptosis induction by our MDM2 inhibitors, suggesting an interesting clinical trial rationale. Toxicology studies are ongoing.

Clinical trials
At this time there are no clinical trials being conducted using the MDM2 inhibitors. Researchers from the University of Michigan are working with Ascenta and Sanofi-Aventis to further test these compounds and develop clinical trials.

Funding for this study was provided, in part, by the National Cancer Institute, Ascenta Therapeutics and Sanofi-Aventis.

American Association for Cancer Research 102nd Annual Meeting, April 2-6, 2011, Orlando, Fla., Abstract No. LB-204 — Highly potent and optimized small-molecule inhibitors of MDM2 achieve complete tumor regression in animal models of solid tumors and leukemia

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