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Collaboration Is Key to Biochemistry Department's Drug Development Success
Thirty years ago, leadership in the Department of Biochemistry set out to build bridges of collaboration and communication between faculty members and to establish and grow five core facilities. Today, discoveries abound.
Startups acquired by major pharmaceutical companies; multiple drug discoveries, including a kidney cancer drug poised for major impact: The results are pouring from the Department of Biochemistry at UT Southwestern Medical Center, where vibrant interdisciplinary research at the crossroads of chemistry and biology is accelerating innovations into the real world.
The synergistic environment supporting these discoveries didn’t happen overnight. It is the culmination of decades of thoughtful planning and guidance by UT Southwestern leaders.
Nearly 30 years ago, Steven McKnight, Ph.D., Professor and then-Chair of the Department of Biochemistry at UT Southwestern, embarked on a mission to build a department that works collaboratively across disciplines to tackle complex scientific problems.
Margaret Phillips, Ph.D., Professor and Chair of the Department of Biochemistry at UT Southwestern, has continued this mission to promote research at the interface of chemistry and biology, including supporting the Department’s five core facilities, which foster state-of-the-art drug discovery and biology.
Their approaches have been implemented across many basic science departments and graduate programs on campus, which complement efforts in Biochemistry and expand faculty research into other areas, encompassing structural, molecular, and cellular biology.
With the infrastructure for collaboration in place, UT Southwestern chemists and biochemists study human diseases that span cancer, immune diseases, metabolic disorders, and infectious diseases.
Existence and Integration of Five Core Facilities
Dr. McKnight recognized early on that the most successful research groups flourish through collaboration. To achieve maximal benefit, the activities of collaborating groups must be integrated.
With these thoughts in mind, the Biochemistry Department has grown deliberately and strategically, recruiting faculty with complementary research interests and ensuring their access to state-of-the-art core facilities that provide shared services in an integrated fashion.
Appreciating that the personnel, equipment, and workflows are different across the cores, Dr. McKnight knew that trying to impart one way of doing things was not going to work. Instead, he mandated that faculty who direct each core facility talk openly with each other to maximize efficiency and coordination.
Dr. Phillips, who became chair of the department in 2016, emphasizes that this business plan, along with housing the five cores under one roof, have been the driving force behind the translation of multiple discoveries into the clinic.
The high-throughput screening methods used in the early phases of drug discovery are a prime example of this synergy, she explains. These methods are designed to link biological discoveries with the tools of chemistry to rapidly identify chemical leads – the starting point for drug discovery.
“Our Department’s unique structure enables the translation of scientific discovery from bench to bedside,” Dr. Phillips says. “Our foundation empowers research teams to tackle ever more complex disease-focused questions – ultimately driving innovation.”
Our Department’s unique structure enables the translation of scientific discovery from bench to bedside. Our foundation empowers research teams to tackle ever more complex disease-focused questions – ultimately driving innovation.
A Shared Vision of Translation
In recent years, several discoveries made within the Department have resulted in the clinical investigation and approval of new drugs, most notably belzutifan, which was approved by the U.S. Food and Drug Administration in 2021 for treating von Hippel-Lindau diseaseassociated renal cell carcinoma, central nervous system hemangioblastomas, and pancreatic neuroendocrine tumors.
The success of belzutifan grew out of the discovery of a protein, hypoxia-inducible factor 2-alpha (HIF-2α), which is key to the growth of kidney cancer and other types of cancer. HIF-2α was first identified by Dr. McKnight and David Russell, Ph.D., former Vice Provost and Dean of Research, and Professor of Molecular Genetics, who collaborated with Dr. McKnight in the early stages of the research in the 1990s.
HIF-2α was considered undruggable for many years until two scientists then at UT Southwestern – Richard Bruick, Ph.D., Professor of Biochemistry, and Kevin Gardner, Ph.D., Professor of Biophysics, who now directs a structural biology center at the City University of New York – carried out structural and biochemical studies showing that the HIF-2α molecule contains a pocket that makes it druggable. Subsequently, and making full use of core facilities in the Biochemistry Department, the two scientists identified multiple compounds that fit into this pocket and inhibited the activity of HIF-2α.
Further development efforts were conducted by a spinoff company named Peloton Therapeutics, which was launched on the UT Southwestern campus in 2011 and acquired by Merck in 2019.
“The history of belzutifan’s development demonstrates the value of cross-disciplinary collaborations at academic medical centers and how these can translate to new treatments for diseases,” says Joan W. Conaway, Ph.D., Vice Provost and Dean for Basic Research. “It also underscores the value of investing in basic science discoveries to drive advancements in medicine.”
The development and recent acquisition of Rodeo Therapeutics is another example of successful clinical translation. The biotech startup was co-founded in 2017 by Joseph Ready, Ph.D., Professor and Vice Chair of the Department of Biochemistry at UT Southwestern, and was bought by Amgen in 2021. The company developed small-molecule therapies designed to promote regeneration and repair of multiple tissues.
Dr. Ready explains that Rodeo was focused on identifying first-in-class, orally available modulators of prostaglandin biology. Their lead 15-prostaglandin dehydrogenase (15-PGDH) modulators, again developed through unfettered access to the Department’s core facilities, generated compelling data in extensive preclinical studies that showed clinical potential across multiple indications. As a result, Amgen acquired the company and plans to further evaluate the drugs in clinical trials.
“The scientific groundwork for building Rodeo was laid right here in the Department,” Dr. Ready says. “At the heart of translating novel therapeutics is strong interdisciplinary collaboration between research teams.”
Future Directions
The field of biochemistry has made rapid advances in recent decades, fueled by innovations in areas such as structural biology, genomics, and mass spectrometry, which allow for global analyses of cellular proteins and metabolites, and the impact of disease or drugs on the cellular makeup of these key molecules.
Steven McKnight, Ph.D., is Professor and former Chair of the Department of Biochemistry. His research focuses on transcriptional regulation.
Margaret Phillips, Ph.D., is Professor and Chair of the Department of Biochemistry. Her research focuses on biochemistry and drug discovery in parasitic protozoa.
Joseph Ready, Ph.D., is Professor and Vice Chair of the Department of Biochemistry. His research focuses on natural products synthesis, medicinal chemistry, and synthetic methodology.
Joan W. Conaway, Ph.D., is Vice Provost and Dean for Basic Research.
Photo Caption: Biochemistry post-baccalaureate researcher Alyza Roman works in a campus lab. The synergistic environment that has accelerated drug discovery from the UT Southwestern Department of Biochemistry has also made for rich training grounds.
