Stuart L. Schreiber - 2025 Welch Awardee Lecture

Molecular Glues & Bifunctional Compounds: Therapeutic Modalities Based on Induced Proximity Stuart L. Schreiber, Ph.D. is the Morris Loeb Research Professor at Harvard University, Founding Core Member of the Broad Institute, Emeritus; Founding Scientist of Arena BioWorks, (a Biomedical Research Institute formed to understand the mechanism of human disease and to translate insights into transformational medicines); and a member of the National Academy of Sciences, National Academy of Medicine and American Academy of Arts and Sciences. His research has been recognized through numerous awards, including the Wolf Prize in Chemistry. Dr. Schreiber’s research integrates chemical biology and human biology to advance the discovery of novel therapeutics. His lab discovered the first molecular glues and developed the first bifunctional compounds that recruit neosubstrates to enzymes in cells. He co-discovered mTOR and illuminated the nutrientresponse signaling network, discovered histone deacetylase (HDAC) and revealed the role of chromatin marks in gene expression, and with Gerry Crabtree mapped the first membrane to nuclease signaling pathway (calcium– calcineurin–NFAT). Schreiber’s development of diversity-oriented synthesis has led to the discovery of many promising agents, including a novel mechanism of action anti-malarial agent now in human clinical trials. His most recent discovery revealed a novel cell state responsible for the ability of cancers to resist a wide range of therapies, and a means to target the cancer therapy-resistant state. Schreiber extended chemical biology principles to medicine by participating in the founding of 14 biotech companies, beginning with Vertex Pharmaceuticals, whose efforts have made cystic fibrosis a manageable disease. These companies or the Schreiber lab itself have thus far developed 17 novel in-human therapeutic agents, nearly all as first-in-class agents. In 2020, Schreiber co-founded Scientists to Stop COVID-19, a nonpartisan science-based group that advised policy makers in U.S. executive, congressional and state governments, as well as leaders in the sports and entertainment industries. Abstract: “Molecular Glues & Bifunctional Compounds: Therapeutic Modalities Based on Induced Proximity” How do proteins in our blood stream regulate the genes residing in the nucleus of cells without entering those cells? Studies of signal transduction in the 1990s revealed that the extracellular signaling proteins bind two integral membrane receptors simultaneously, inducing proximity of the transmembrane-spanning receptors’ intramolecular enzymatic domains. This induced, “high local concentration” increases the rate of enzyme-catalyzed chemical reactions between the intracellular domains. This principle is repeated over and over as the instructions are eventually received by DNA-binding transcription factors that regulate gene activity. Chemical biologists have exploited this insight into information transfer by discovering and synthesizing small molecules that function by inducing proximity of their target signal proteins. This ability to commandeer induced proximity is transforming medicine where drug hunters are actively and rationally pursuing the development of proximity-inducing drugs. This Lecture explores molecular glues and bifunctional compounds – proximity-inducing compounds – and offers a framework to understand and exploit their underlying mechanisms. Proximity-inducing drugs trace back to the revelation that the immunosuppressive cyclosporin and FK506 act in a way previously not seen – as “molecular glues” that induce protein–protein associations (Cell, 1991, 66, 807-815) – and the subsequent development of bifunctional compounds that induce enzyme–neosubstrate interactions. These observations fueled the surge of interest in strategies for inducing functional protein–protein associations. I will discuss advances in the discovery of binders, bifunctional compounds, and molecular glues that alter their targets’ cellular lifetimes, activities, and localizations and may facilitate the translation to novel therapeutics having tissue and substrate selectivity. Learn more about The Welch Conference: https://welch1.org/conference/confere...