Dr. Stuart Conway
Professor of Medicinal Chemistry, Michael and Alice Jung Endowed Chair in Medicinal Chemistry and Drug Discovery
Professor bio:
Stuart Conway is a Professor of Medicinal Chemistry and the inaugural holder of the Michael and Alice Jung Endowed Chair in Medicinal Chemistry and Drug Discovery at the University of California, Los Angeles. He studied Chemistry with Medicinal Chemistry at the University of Warwick (1994-1997) before undertaking PhD research at the University of Bristol (1997-2001) with Profs Jeff Watkins FRS and David Jane. Stuart completed post-doctoral studies with Professor Andrew Holmes FRS at the University of Cambridge (2001-2003) and in 2003, he was appointed as a Lecturer in Bioorganic Chemistry at the University of St Andrews. In 2008 was appointed as an Associate Professor at the University of Oxford, and between October 2014 and June 2023 he was a Full Professor at Oxford. He was concurrently the E. P. Abraham Cephalosporin Fellow in Organic Chemistry at St Hugh’s College, Oxford. His research focuses on the development of molecular tools to enable the study of biological systems, with a focus on epigenetics, hypoxia, and proximity induction approaches. This work has been recognized by a number of prizes, including the 2024 UCB-Ehrlich Award from the EFMC and the 2024 Robert Scarborough Award from the ACS Division of Medicinal Chemistry, both awarded for excellence in medicinal chemistry.
Abstract:
Immunomodulatory imide drugs (IMiDs), including pomalidomide and lenalidomide, act as molecular glues to recruit the E3 ligase adaptor protein cereblon to a conserved zinc finger degron motif found in endogenous human proteins, resulting in their degradation. These proteins include transcription factors such as IKZF1/3 and SALL4. This motif is only 60 residues in size, making it attractive as a degron for use in target validation. However, the existing IMiDs not only induce degradation of the POI-zinc finger degron fusion, but also promote degradation endogenous proteins, including IKZF1/3. To overcome this issue, we have taken a bump-and-hole approach to develop degrons/small molecule pairs that selectively induce degradation of a degron-POI fusion in the presence of IKZF1/3. We designed a library of 8380 mutant degrons based on the IKZF1/3 degron, and screened this library against bumped IMiD analogs to identify compounds that induce degradation of the mutant degron, but not the wild-type IKZF1/3. The most selective bumped IMiD/degron pair was used to induce selective degradation of an unliganded human protein, TRIM28. During these studies, we serendipitously discovered a bumped IMiD which selectively degrades an endogenous protein that contains multiple zinc fingers. I will describe our studies to determine which zinc finger is recruited by the bumped IMiD and a structure-based analysis of how this compound is accommodated in the cereblon-IMiD-zinc finger ternary complex.
