Innovative Translation: U-M's drug discovery landscape
by Alan Saltiel
Mary Sue Coleman Director of the Life Sciences Institute
When I joined the University of Michigan in 2001, I had just spent 10 years in pharmaceutical R&D. It turns out I was pretty lucky. We now know that the 1990s were something of a golden age in drug discovery, with great support in the industry for innovative approaches to complex diseases.
Much has changed. Companies have curtailed their discovery efforts in response to the new realities of the marketplace, which demands more D than R. By investing in later-stage development more than hugely expensive early-stage research, companies avoid what they perceive of as risky investments. After all, a lot of basic research is about “failure”—but at the same time they risk creating a gap in the pipeline of innovative new therapeutics.
Universities are beginning to fill this gap by leveraging long-standing investments in research in order to exploit opportunities in the commercial space—a movement that aligns with our mandate of public service as we try to put into practice important discoveries.
Success in innovative translation will require a clear understanding of our capabilities, strengths and limitations. At the Life Sciences Institute we are trying to adopt some of the better practices of the pharmaceutical industry while maintaining the LSI’s culture of embracing risk. Can this be done? I'm starting to think that the answer is yes!
I have plenty of reasons to go out on a limb and say this. The Center for the Discovery of New Medicines (CDNM) awarded its first round of grants in December. Eight projects across U-M were funded. The support allows researchers to move promising potential drugs to the next phase of development; projects will investigate new therapeutics for the treatment of cancer, of antibiotic-resistant bacteria involved in food poisoning, amphetamine addiction and other diseases. The second round of applications for support is underway.
And in recent months in the LSI, researchers have published landmark papers that exemplify how creative and rigorous basic science points us in new directions for potential therapeutics.
- Shawn Xu identified a genetic pathway in nematodes that increases longevity in response to cold. Humans share the same program.
- Mi Hee Lim led an interdisciplinary team that found how green tea extract interferes with the aggregation of metal-associated amyloids-the proteins that for plaques in Alzheimer's disease-and is now working with Bing Ye to test the molecule in drosophila.
- Ivan Maillard published a paper that represents both fascinating science and potential to impact humans; his research demonstrated how strategically inhibiting the Notch signaling pathway prevented graft-vs-host disease in mice.
- John Tesmer obtained the first images of the full-length protein phospholipase C b3 bound to its activating protein, Gaq, which could have an impact on our understanding of the molecular basis of heart failure.
And work from my lab also exemplifies the power of collaborative academic drug discovery. This month we published a paper in Nature Medicine that is the result of deep, long-term collaboration as well as many ad-hoc working relationships across campus. The translation of the identification of the role of two key genes in obesity to the discovery of a drug that dramatically reverses obesity in mice could simply not have happened as quickly-or as creatively-anywhere else as it did at University of Michigan.
This drug, amlexanox, was found in a screen conducted by Stuart Decker and Martha Larsen in LSI’s Center for Chemical Genomics. Ron Rubin from the LSI’s Center for Structural Biology performed computer modeling on the compound bound to its targets. Fellows and students in my lab demonstrated that this compound promoted weight loss and improved insulin sensitivity in mice, in the process revealing new insights into how energy balance is controlled in obesity. Hollis Showalter from the College of Pharmacy’s Valteich Medicinal Chemistry Center is now doing follow-up work on the compound, working together with our own John Tesmer to solve structures of complexes of the drugs with its targets.
Along the way we have had significant strategic contributions from Rakhi Juneja in the Office of Technology Transfer and our expert outside patent counsel, David Casimir.
The screen was funded in part by the Michigan Diabetes and Research Center, the Nathan Shock Center and MICHR.
And now we are preparing to move to the next phase, which will be testing the effectiveness of amlexanox in humans with clinical trials conducted at the university, working with Elif Oral from the U-M Department of Medicine, Division of Endocrinology.
Throughout the process, our team received ongoing invaluable commercialization mentorship from a group of donors who see the potential in academic drug discovery and have invested in the LSI’s Innovation Partnership. The Partnership catalyzed the project in so many ways, and I’m personally very grateful for the group’s contributions.
And I haven’t even listed all of the U-M authors on the paper or mentioned the talented scientists and students in our labs who contributed—significantly—to this work from across the campus, or the staff that supporting our applications for funding, or the team that will be helping with the clinical trials.
And finally, who benefits? First, of course, the patients. If amlexanox works--and that is still completely uncertain--we may be able to offer a viable new treatment for metabolic disorders that improves the lives of many. That is the goal and the ultimate hope.
But also, the university stands to benefit. While we aren’t motivated by profit, we are excited about the possibility of reinvesting any commercial proceeds into more research that might sustain this sort of work in our own labs. For supporters of the university, that kind of investment resonates.
For some years now, we’ve been talking about the “valley of death,” where academic discoveries like our findings about the gene IKKe languish between traditional public funding and corporate investment. After the surprises of the last 10 years, I know better than to predict that our philosophy of “innovative translation” will lead to another golden age of drug discovery. But I have seen enough proof to think a new and successful model for bringing discoveries from the lab to patients just might be possible.