Development and crystal structures of a potent second-generation dual degrader of BCL-2 and BCL-xL
Year: 2024
Type: article
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.
Source: Nature Communications
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,790
Funders: U.S. Department of Energy, U.S. Department of Health and Human Services, Cancer Prevention and Research Institute of Texas, National Institutes of Health, Office of Science, University of Texas Health Science Center at San Antonio, National Institute on Aging, National Cancer Institute, National Institute of General Medical Sciences, Office of Research Infrastructure Programs, National Institutes of Health, Argonne National Laboratory
Awards: G102163711, G107546177, G1114781936, G1143455775, G1166396873, G1183574029, Mays Cancer Center at UT Health SA, G1258574971, G1313983767, G1664757510, G1821512284, Recruitment of Rising Stars, G204618756, G2287611682, G2444532981, G262962599, G2849897711, Develop BCL-xL proteolysis targeting chimeras as safer and better senolytics, G3075337988, G3152346458, G3754226247, Orbitrap Exploris 480 Mass Spectrometer for Biomedical Research, G3861159085, G3874765150, G3924411600, G409777406, G4155925329, G4429385918, G498139845, Structural Biology of the Ubiquitin Conjugation System, Pixel Array Detector for Macromolecular Crystallography, G5607048534, G5615350433, G5827286289, Center for Innovative Drug Discovery: Expansion of a Highly Productive Shared Cancer Drug Discovery Resource for Texas, G6177109745, G6848031779, G6918803902, G7257490191, Inhibition of Bcl-xL by Targeted Degradation, G78868261, Upgrade of a Core Laboratory Macromolecular X-ray Diffraction System, Development of Caspase Cleavage Targeting Chimeras (CACTACs) for Targeted Protein Cleavage, G9000051782, G9000101301, G9000125186, G9000150452, G9000324485, Structure and Function of the Essential Cell Cycle Regulator Cdc34, NE-CAT: A Resource for Advanced Macromolecular Crystallography, G969889393, G993149817
OpenAlex ID: W4393314657