New cancer drugs discovered at U-M head to clinical trials
Shaomeng Wang, Ph.D., the Warner-Lambert Parke-Davis Professor of Medicine and director of the Cancer Drug Discovery Program at the U-M Comprehensive Cancer Center
One compound targets cell death blockers, other impacts tumor suppressor protein
Researchers at the University of Michigan Comprehensive Cancer Center have developed two new types
The first compound, called AT-406, was
shown to effectively target proteins that
block normal cell death from occurring.
Blocking these proteins caused tumor cells
to die, while not harming normal cells.
The researchers believe the drug could
potentially be used alone or in combination
with other treatments.
In animal models, the drug
shrank tumors but caused
few side effects. The drug
is designed to be taken by
mouth, which researchers
say will make it easier than
chemotherapies to administer.
The second type of drug compound developed at U-M is designed to activate the tumor suppressor p53 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. Researchers tested two new compounds and found they blocked 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 Wang, whose team also developed these compounds.
Many traditional cancer drugs 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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