Student Hosted Colloquia: Professor Stuart L. Schreiber, Harvard University
About the Seminar
Molecular Glues & Bifunctional Compounds: Therapeutic Modalities Based on Induced Proximity
Stuart L. Schreiber (1, 2, 3)
(1) Harvard University, (2) Broad Institute, ArenaBioWorks (3)
This Lecture explores molecular glues and bifunctional compounds – proximity-inducing compounds – and offers a framework to understand and exploit their similarity to hot spots, missense mutations, and posttranslational modifications (PTMs). Efforts to translate novel biological findings to medicines have revealed a need for new approaches to drug discovery. The methods we are now pursuing trace back to the revelation that the 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. The realization that additional medicines act as molecular glues has 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.
See also “The Rise of Molecular Glues”, Cell, 2021, 184, 3-9; “Molecular Glues & Bifunctional Compounds: Therapeutic Modalities Based on Induced Proximity”, ChemRxiv, 2024.
About the Speaker
Stuart L. Schreiber, Ph.D. is the Morris Loeb Research Professor at Harvard University, Founding Core Member of the Broad Institute, Emeritus; Founding CEO 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.
Dr. Schreiber’s research integrates chemical biology and human biology to advance both our understanding of chemistry and biology, and the discovery of novel therapeutics. He is known for his use of small molecules to explore biology and medicine, and for his role in the development of the field of chemical biology. He first discovered that small molecules could function as “molecular glues” that induce protein–protein associations, and he extended this concept with Jerry Crabtree through the development of bifunctional “chemical inducers of Proximity” (CIPs). The Schreiber and Crabtree collaboration also led to the mapping of the first membrane-to-nucleus signaling pathway (calcium–calcineurin–NFAT). His lab co-discovered mTOR in 1994 (simultaneously with Sabatini) and helped illuminate the mTOR-dependent nutrient-response signaling network. His lab discovered histone deacetylase (HDAC) and, together with David Allis and Michael Grunstein in 1996, the role of chromatin marks in gene expression.
His work demonstrated for the first time that drugs can result from: 1) the targeting of protein kinases (sirolimus/mTOR) and protein phosphatases (sandimmune/ calcineurin); 2) gene regulation by chromatin-modifying enzymes (vorinostat/HDAC), 3) molecular glues/CIPs that activate cellular processes by enforced proximity (GVH Disease), and 4) targeting of the proteasome (bortezomib/proteasome). The discovery of molecular glues and development of chemical inducers of proximity led the development of many additional widely used drugs.
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 being developed in collaboration with the pharmaceutical company Eisai (Nature, 2017). 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 (Nature, 2017). His research has been reported in over 700 publications (H index = 166; Schreiber Publications) and recognized through numerous awards, including the Arthur C. Cope Award and the Wolf Prize in Chemistry.
Schreiber has founded 14 biotechnology companies that use chemical biology to discover novel therapeutics, including molecular glues used to treat cystic fibrosis discovered at Vertex Pharmaceuticals (founded 1989). Overall, 17 in-human and first-in-class therapeutics have resulted from these companies. In 2020, Schreiber co-founded Scientists to Stop COVID-19, a nonpartisan science-based group who advised policy makers regarding the global pandemic in U.S. executive, congressional and state governments, as well as leaders in the sports and entertainment industries. The organizational concepts that emerged for mitigating the impact of the pandemic underlie the founding of Arena BioWorks, which aims to impact a broader spectrum of disease.