Related Experiment Video
Updated: Jun 29, 2025
Examining BCL-2 Family Function with Large Unilamellar Vesicles
Published on: October 5, 2012
Development and crystal structures of a potent second-generation dual degrader of BCL-2 and BCL-xL
Digant Nayak1, Dongwen Lv1, Yaxia Yuan1
1Department of Biochemistry & Structural Biology and Greehey Children's Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA.
Abstract:
Overexpression of BCL-xL and BCL-2 play key roles in tumorigenesis and cancer drug resistance. Advances in PROTAC technology facilitated recent development of the first BCL-xL/BCL-2 dual degrader, 753b, a VHL-based degrader with improved potency and reduced toxicity compared to previous small molecule inhibitors. Here, we determine crystal structures of VHL/753b/BCL-xL and VHL/753b/BCL-2 ternary complexes. The two ternary complexes exhibit markedly different architectures that are accompanied by distinct networks of interactions at the VHL/753b-linker/target interfaces. The importance of these interfacial contacts is validated via functional analysis and informed subsequent rational and structure-guided design focused on the 753b linker and BCL-2/BCL-xL warhead. This results in the design of a degrader, WH244, with enhanced potency to degrade BCL-xL/BCL-2 in cells. Using biophysical assays followed by in cell activities, we are able to explain the enhanced target degradation of BCL-xL/BCL-2 in cells. Most PROTACs are empirically designed and lack structural studies, making it challenging to understand their modes of action and specificity. Our work presents a streamlined approach that combines rational design and structure-based insights backed with cell-based studies to develop effective PROTAC-based cancer therapeutics.
Insights
Researchers developed WH244, a potent PROTAC degrader targeting BCL-xL and BCL-2 proteins implicated in cancer. Structural insights guided the rational design of this improved therapeutic agent for cancer drug resistance.
Area of Science:
- Structural Biology
- Chemical Biology
- Cancer Therapeutics
Background:
- Overexpression of BCL-xL and BCL-2 proteins contributes to cancer development and resistance to therapies.
- Proteolysis-targeting chimera (PROTAC) technology offers a novel approach to degrade target proteins.
Purpose of the Study:
- To determine the crystal structures of VHL/753b/BCL-xL and VHL/753b/BCL-2 ternary complexes.
- To understand the structural basis for differential target engagement and guide the rational design of improved PROTACs.
Main Methods:
- X-ray crystallography to determine ternary complex structures.
- Biophysical assays and cell-based studies to validate functional importance and assess degradation.
- Structure-guided rational design of novel PROTACs.
Main Results:
- Determined distinct ternary complex architectures for VHL/753b/BCL-xL and VHL/753b/BCL-2.
- Identified key interfacial interactions critical for target degradation.
- Designed WH244, a novel degrader with enhanced potency against BCL-xL and BCL-2 in cellular assays.
Conclusions:
- Structural insights into PROTAC-target interactions are crucial for rational drug design.
- A streamlined approach combining structural biology, rational design, and cell-based validation can accelerate the development of effective PROTAC-based cancer therapeutics.
- WH244 represents a promising advancement in targeting BCL-xL/BCL-2 for cancer treatment.
Related Concept Videos
01:31The Intrinsic Apoptotic Pathway
01:24B Cell Activation and Differentiation
When naive B cells encounter a specific antigen that can bind to the B cell receptor (BCR) on their surface, they undergo sensitization to respond to the antigen's presence. Sensitization begins with...
01:15Receptor Downregulation in MVBs
The EGFR can initiate signaling pathways that lead to cell proliferation, migration, and differentiation. Overexpression of EGFR stimulates cells to proliferate. Excessive EGFR...