题   目: The converging mechanism of a molecular glue and cancer gain-of-function mutations
报告人:  Xiaowen Xie, Ph.D.
Pharmacology Department, University of Washington
时  间: 12月16日（周一）13:00-14:00
地    点: 吕志和楼B101
主持人: 唐淳 教授
摘要:
Targeted protein degradation, particularly via molecular glue degraders, has revolutionized drug discovery with its simplicity and favorable pharmacological properties. However, only a limited number of molecular glues have been identified to date. Expanding this repertoire is crucial for advancing our understanding of molecular glue mechanisms, E3 ligase interactions, and their therapeutic applications.
For the first time, our study defines the target and mechanism of a new molecular glue degrader UM171 that utilizes a dimeric CULLIN3 E3 ligase (KBTBD4) to degrade a transcription corepressor CoREST complex. This research unveils an asymmetric E3 architecture that not only provides fundamental insights into E3 structure and function but also sets the groundwork for targeting a previously inaccessible, extensive class of ligases for protein degradation.
Remarkably, the recurring mutations on KBTBD4 found in medulloblastoma, confers gain-of function to KBTBD4 to induce degradation of the same substrate CoREST complex. The cancer mutations resemble chemical glue UM171 functionally, structurally, and mechanistically, elucidating the converging mechanisms between molecular glue degraders and cancer gain-of-function mutations, portraying cancer mutations as "genetic glues." This resemblance raises the possibility of using massively parallel genetic methods for novel molecular glue discovery and design, potentially transforming therapeutic strategies in oncology.
报告人简介：
Dr. Xiaowen Xie is an acting instructor in the Pharmacology Department at University of Washington. She received her Ph.D from Peking Unversity in 2019 and went to UT southwestern medical center as a postdoc for one year, and then transferred to University of Washington to continue her research career with Dr. Ning Zheng until now. Dr. Xie’s research has been focusing on targeted protein degradation, particularly molecular glue degraders, using multidisciplinary approach-including chemical biology, proteomics, base editing, and structural biology to understand the molecular glue mechanisms, E3 ligase interactions, therefore, to figure out their therapeutic applications. Her back-to-back stories about the most recent work on molecular glue degraders just got accepted by Nature recently.