The Center for the Discovery of New Medicines has awarded funding for five new drug discovery projects by U-M faculty that address critical health areas including chronic kidney disease, ovarian cancer, breast cancer, toxoplasmosis and atherosclerosis.
The center supports faculty from across U-M in developing promising biomedical research toward commercialization.
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The grants provide researchers with access to the technology and expertise of four core laboratories at the university, helping advance early-stage projects to the point they can attract more substantial funding from federal agencies, foundations and industry partners.
Together, the Center for the Discovery of New Medicines and its affiliated cores at the Life Sciences Institute and College of Pharmacy help guide researchers through the many stages of the drug discovery process — from validation of a drug target to optimizing drug safety and effectiveness for human clinical trials.
“There s a lot of high-caliber science being done at U-M,” said Vincent Groppi, the center’s director. “The CDNM’s role is to provide the technical resources and collaborative guidance to help turn basic research discoveries by U-M faculty into therapeutic drugs that can improve human health and save lives.”
Since its establishment in 2012, the center has awarded 32 grants totaling nearly $860,000. Several projects have already gone on to receive additional external funding, commercial licensing and patent protection.
The new awards, which range in size from $37,000 to $50,000, were given to:
• Dr. Ronald Buckanovich, associate professor of medical oncology at the Medical School, for the development of new and effective therapies for treatment-resistant epithelial ovarian cancer — the sixth most common cancer in women worldwide.
Ovarian cancer stem cells show an increase in the enzyme aldehyde dehydrogenase (ALDH); researchers believe its inhibition could help make traditional therapies more effective.
The grant-supported studies will use the resources of the LSI’s Center for Structural Biology and Pharmacy’s Vahlteich Medicinal Chemistry Core to design and synthesize new classes of ALDH inhibitors using structure-based drug design. The properties of the best agents will be optimized at Pharmacy’s Pharmacokinetics Core, and the best inhibitors will be tested in a mouse model that incorporates grafted, patient-derived tumors.
• Vernon Carruthers, professor of microbiology and immunology at the Medical School, for the development of an inhibitor of a key protease essential to chronic toxoplasmosis infection.
While many people infected with the parasite Toxoplasmosis gondii have no symptoms, it can cause severe health problems in people with weakened immune systems and in pregnant women. There is currently no available treatment for this infection, which is carried by more than 60 million people in the U.S.
Building on success from previous CDNM grant support, the new funds will be used in the Center for Structural Biology to synthesize and crystalize inhibitors of the tgCPL protease, and ultimately to develop one or more compounds suitable for testing in animal models.
• Dr. Yuqing Eugene Chen, the Frederick Huetwell Professor of Cardiovascular Medicine and vice chair for basic and translational research in the Department of Cardiac Surgery at the Medical School, to identify small molecule activators of a transcription factor known as KLF14 in the treatment of atherosclerosis, the buildup of plaques in the arteries.
KLF14 helps the body shuttle excess cholesterol back to the liver, and ultimately out of the body. The project will use the resources of the LSI’s Center for Chemical Genomics to conduct high-throughput screening for new activators that may lack the negative side effects of known activators.
• Raymond Trievel, associate professor of biological chemistry at the Medical School; Jeanne Stuckey, associate professor at the Life Sciences Institute; and Wenjun Ju, research assistant professor of internal medicine at the Medical School, to advance work on a promising target for chronic kidney disease, one of the most common and deadly non-communicable diseases, affecting up to 16 percent of the world’s population.
Ju’s group was part of the team, led by U-M’s Matthias Kretzler, which identified an enzyme that functions as a biomarker of declining kidney function and can also be used as a drug target.
The funds will be used to develop a high-throughput biochemical screen at the Center for Chemical Genomics for compounds that inhibit the enzyme’s activity. The enzyme is also a promising target for other diseases including cancer, diabetes and Parkinson’s.
• Matthew Soellner, assistant professor of medicinal chemistry in the College of Pharmacy, to develop a kinase inhibitor for the treatment of triple-negative breast cancer.
Triple-negative breast cancers are especially lethal, and disproportionately affect women of African descent. It is the only subset of breast cancers for which there are no FDA-approved targeted therapies.
The grant will support continued development of a promising inhibitor known as UM-164 in the Vahlteich Medicinal Chemistry Core and Pharmacokinetics Core.
The Center for the Discovery of New Medicines is supported by the Office of the Provost, College of Pharmacy, Life Sciences Institute, Comprehensive Cancer Center, and the Department of Internal Medicine, Department of Pathology, and Endowment for the Basic Sciences in the Medical School.
