In this month’s episode of the Chain, Jim Wells, professor of pharmaceutical chemistry and cellular and molecular pharmacology at the University of California, San Francisco, sits down with moderator Ben Hackel, professor of chemical engineering and materials science at the University of Minnesota, to discuss Wells’ work in advancing targeted protein degradation.

Wells outlines the key design elements of targeted protein degraders and their general mechanism of action, how his lab developed antibody-based PROTACs—also known as AbTACs—to target extracellular proteins, and the innovative work from industry leaders that inspired his lab’s discoveries. He also speaks about the lingering questions driving ongoing and future projects, the challenges facing the protein degradation space, and why he considers himself a “pirate of biology” rather than an inventor.

BIOs

James A. Wells, Ph.D., Professor of Pharmaceutical Chemistry and Cellular and Molecular Pharmacology, University of California, San Francisco
Wells’ group pioneered the engineering of proteins, antibodies, and small molecules that target catalytic, allosteric, and protein-protein interaction sites. They also developed technologies including protein phage display, alanine-scanning, engineered proteases for improved hydrolysis, bioconjugations, N-terminomics, and disulfide “tethering”—a novel site-directed fragment-based approach for drug discovery. Most recently, they launched an industrialized recombinant antibody production pipeline for the proteome.  

These discoveries led to important insights into protease mechanisms, growth factor signaling, hot spots in protein-protein interfaces, the role of caspases in biology, and determining how cell surfaces change in health and disease. Wells’s team was integral to several protein products, including Somavert for acromegaly, Avastin for cancer, Lifitegrast for dry eye disease, and engineered proteases sold by Pfizer, Genentech, Shire, and Genencor. He is an elected member of the US National Academy of Science, the American Association of Arts and Science, and the National Academy of Inventors.

Benjamin J. Hackel, Ph.D., Professor of Chemical Engineering and Materials Science, University of Minnesota
Ben Hackel is a professor of chemical engineering and materials science at the University of Minnesota. He earned degrees in chemical engineering from the University of Wisconsin (B.S. 2003, advised by Eric Shusta) and MIT (Ph.D. 2009, advised by Dane Wittrup). He performed postdoctoral research in the radiology department at Stanford University (Sam Gambhir). Since its inception in 2011, the Hackel lab has applied protein engineering technologies to develop physiological, molecular targeting agents for molecular diagnostics and targeted therapy, focusing on oncology and infectious disease.