The Chemistry of Success
When Duxin Sun, PhD, was being recruited to the department of pharmaceutical sciences in 2008, he met with Shaomeng Wang, PhD, a U-M professor of medicinal chemistry, medicine, and pharmacology. The two immediately saw that their complementary research interests had great partnership possibilities.
As director of the Cancer Drug Discovery program at the U-M, Wang leads a multi-disciplinary research group that has developed compounds whose mechanisms of action showed great promise in subduing cancer. As director of the College's Pharmacokinetics Core and associate professor of pharmaceutical sciences, Sun's scientific mission is to support a range of activities, including lead compound modeling, dose optimization, and clinical trials, that can turn the fruits of research into medicine.
One class of the compounds Wang's laboratory was working on in 2008 focused on blocking the protein/protein interaction between the MDM2 oncoprotein and p53 tumor suppressor. When these two proteins bind to each other, MDM2 degrades p53 and diminishes p53's tumor-suppressor function. Wang's goal was to find compounds that could block the binding between MDM2 and p53, thus leading to reactivation of p53 and killing tumor cells.
His laboratory had designed and synthesized a class of highly potent MDM2 inhibitors, including one compound that was very effective in killing tumor cells in cell culture, and inhibiting tumor growth in human cancer animal models.
Unfortunately, the lead compound had pharmacokinetic shortcomings.
Enter Duxin Sun.
As luck would have it, Sun, too, had a research interest in protein/protein interactions and drug discovery for cancer therapy. In fact, he established the Pharmacokinetics Core at the College of Pharmacy specifically to support both his and other U-M scientists' drug discovery efforts.
Sun recognized that not only could Wang's extensive knowledge of protein-protein interaction and drug design advance his own research, but also that he could contribute to Wang's search for lead compounds based on their pharmacokinetic properties.
Once Wang started his collaboration with Sun, they rapidly identified the major metabolic site in Wang's original lead compound. They subsequently co-designed and synthesized new compounds to address the key metabolic stumbling block. Within a few months, their collaboration led to the discovery of a series of much improved compounds.
That could be just the beginning.
Many traditional cancer drugs also activate the p53 tumor suppressor. Alas, they cause DNA damage not only in tumor cells, but also in normal tissues, leading to undesirable side effects. The new MDM2 inhibitors discovered at U-M activate p53 while avoiding the DNA damage of other drugs. Because p53 is involved in a variety of human cancers, the new drug has potential broader therapeutic use.
As a co-director of the Experimental Therapeutics Program at the U-M Comprehensive Cancer Center (UMCCC), Wang also collaborates with Sami Malek, MD, a UMCCC-affiliated physician-scientist. They have identified certain markers in acute leukemia that predict which ones will be most vulnerable to the MDM2 inhibitor. This knowledge would allow physicians to target the drug only for use in patients most likely to benefit.
"For the first time, we showed that activation of p53 by our optimized MDM2 inhibitors can achieve complete tumor regression in a mouse model of human cancer," explains Wang.
In June 2010, these compounds were licensed for clinical development by Sanofi, a large French pharmaceutical firm. The lead compound entered Phase I clinical trials in June 2012.
Since their first success, the two scientists have collaborated on many other projects, investigating compounds that may also be drug candidates for use in cancer therapy. They have weekly interactions during which experimental data is communicated, back and forth. They then make collective decisions to move promising compounds forward. The experiments they conduct are based on their collective data.
Their efforts have led to several joint inventions and one additional compound with a different target. This latest compound recently completed IND-enabling studies, and will enter human clinical trials for cancer treatment in 2013.
Now Sun and Wang are moving toward a more formal professional affiliation: organizing a free-standing cancer drug discovery program with other investigators at U-M.
