Multi-institutional team to develop novel drugs that could revolutionize treatment of alcoholic hepatitis
MINNEAPOLIS / ST. PAUL (02/08/2022)—A multi-institutional team of scientists from the Department of Chemistry at the University of Minnesota Twin Cities and the Mayo Clinic have been awarded a nearly $1 million grant by the Minnesota Partnership for Biotechnology and Medical Genomics to develop a therapeutic solution to address the challenge posed by alcoholic hepatitis. Titled, “Lead Optimization of a Novel Epigenetic Inhibitor Series for Alcoholic Hepatitis,” the project will be led by the University’s McKnight Presidential Fellow and Merck Professor of Chemistry William Pomerantz and Dr. Vijay Shah, professor of medicine and physiology at the Mayo Clinic. Vadim Gurvich of the Institute for Therapeutics Discovery and Development at the University, and Drs. Harmeet Malhi and Joel Reid of the Mayo Clinic will also be collaborating with Pomerantz and Shah. Gurvich’s expertise in drug development and medicinal chemistry, Malhi’s expertise in liver dysfunction, and Reid’s expertise in preclinical pharmacology will be critical in the successful development of the inhibitor therapy.
Alcoholic hepatitis (AH), a leading cause of mortality among patients with liver disease is marked by severe liver inflammation. Heavy consumption of alcohol damages the liver, and over time sets into motion physiological reactions that trigger an inflammatory cascade, where the body in an effort to protect itself continues to set off proteins that cause inflammation even after the individual has stopped consuming alcohol. The mechanism results in severe hepatitis, and besides the costs associated with prolonged hospitalization, patients are faced with the prospect of permanent liver injury, liver failure, and death.
The existing treatment options, both surgical and therapeutic, have not been successful for two key reasons: patients typically die before they meet the criteria for a liver transplant, and immunomodulatory corticosteroids have demonstrated limited effectiveness, and have not shown improvement in the long term survival rates of patients with AH. However, there have been studies that indicate that targeting proteins responsible for triggering the inflammatory cascade offers a potential pathway to improving patient outcomes. Based on these studies and their own research, the Pomerantz-Shah collaboration seeks to develop novel drugs that will switch off the master regulator of inflammation in the liver. They propose an epigenetic therapy which will allow for the modulation of trigger proteins called chemokines. If the study is successful, it will be a monumental step towards effective treatment and survival of patients with AH.
Commenting on the significance of the project and the interdisciplinary nature of the team, Pomerantz says, “Epigenetic therapies have tremendous potential, and I am excited to continue working with Dr. Vijay Shah and his team at the Mayo Clinic, to help translate our research findings into a potential therapeutic solution for patients suffering from severe liver disease.”
HOW THE THERAPY WILL WORK
Bromodomain and Extra-Terminal (BET) family proteins BRD2, BRD3, BRD4, and BRDT function as epigenetic and transcriptional regulators in the human body. In other words, they operate to bring about temporary changes or modulation in cellular activity in response to a variety of signals.
While the concept of switching off or modulating the inflammation trigger has held promise, inhibitors that target BET proteins broadly are riddled with problems of toxicity and unwanted side-effects. At the same time, studies have indicated that of these proteins, BRD4 has been a particularly relevant target for the regulation of inflammation set off by chemokines. To address the challenges posed by expansive inhibition of BET proteins, scientists in the Pomerantz lab have, over the last six years, produced a series of potent inhibitors that can selectively target individual bromodomains including BRD4.
Summarizing their research so far, Pomerantz says, "We have worked on developing new inhibitors for a specific class of epigenetic protein which contains a druggable site called a bromodomain. After 6 years of research we have refined our inhibitors to have some of the highest potencies and selectivities for our protein of interest, BRD4, which we hope will reduce the significant toxicities observed in the clinic for related inhibitors."
Supported by the MN Partnership grant, the scientists will use data from these preliminary studies to launch the next phase of their research, which will involve testing two series of BRD4 inhibitors. This phase has two key goals: evaluation of the therapeutic efficacy of the selected inhibitor series, and their optimization to maximize drug efficacy. Experiments conducted in this phase will provide data on critical points such as effectiveness of the specific BRD4 inhibitors (which would mean reduction in chemokine production in the liver, and hence reduced inflammation), effective dosage, levels of toxicity, absorption, metabolization, and clearance from the body. Put together, the outcomes of the study will determine not only the effectiveness of BRD4 inhibitors for treating AH, but also critical details that will dictate clinical formulations and dose schedules for clinical trials in humans in the future, for the treatment of AH.
The multidisciplinary collaboration between the Pomerantz and Shah labs is particularly suited for a project like this. The Pomerantz lab is known internationally for its expertise in medicinal chemistry and structural biology. Dr. Shah is an internationally recognized expert in AH, and under his leadership his team has identified the key drivers of inflammation in AH. The collaboration of their research teams has previously demonstrated that inhibition of BRD4 suppresses inflammatory chemokine expression. (Details of the research were published in Nature Communications under the title “Super enhancer regulation of cytokine-induced chemokine production in alcoholic hepatitis.”) The diverse yet complementary expertise of the two principal investigators is critical to such boundary crossing research. Currently, in the absence of approved or effective therapies for AH, treatment is largely limited to patient support. The novel drug that the scientists hope to develop with the grant from the MN Partnership for Biotechnology and Medical Genomics holds the potential to provide transformative care for patients, and reduce both disease morbidity as well as mortality rates associated with AH.
Story by Roopa Sukumaran Berzins
A Fulbright Fellow at ETH, Zurich with Professors François Diederich and Jack Dunitz, Professor William C. K. Pomerantz earned his Ph.D. in chemistry under Professors Sam Gellman and Nick Abbott at the University of Wisconsin-Madison, and was a postdoctoral fellow under Professor Anna Mapp at the University of Michigan. He joined the chemistry faculty at the University of Minnesota Twin Cities in 2012, and is currently a McKnight Presidential Fellow and Merck Professor of Chemistry. His research focuses on the development of chemical biology and medicinal chemistry approaches for modulating protein-protein interactions involved in transcriptional complexes. His research has been recognized through several awards including a Sidney Kimmel Cancer Scholar award, an NSF CAREER award, a Cottrell Scholar Award, and an International Chemical Biology Society (ICBS) Rising Star in Chemical Biology award. Pomerantz is currently the global council co-chair for ICBS, Early Career Board Member for ACS Med. Chem. Lett, and councilor for the American Chemical Society. His research website carries updated and detailed information on his current projects.
Dr. Vijay Shah serves as the Carol M. Gatton and Mayo Distinguished Investigator and Chair of Department of Medicine at Mayo Clinic. He has maintained an NIH-funded program for 25 years which focuses broadly on basic, clinical, and translational aspects of alcohol related liver disease, cirrhosis, portal hypertension and its complications with 250 peer reviewed publications in prestigious journals such as Journal of Clinical Investigation, Nature, Proceedings of National Academy of Science, New England Journal of Medicine and others. Dr. Shah is a member of the prestigious American Society of Clinical Investigation (ASCI) and Association of American Physicians (AAP). Learn more about his research interests.
The Minnesota Partnership for Biotechnology and Medical Genomics is a state of Minnesota funded initiative that provides support for innovative research conducted by collaborative teams from the University of Minnesota and Mayo Clinic.