Development and crystal structures of a potent second-generation dual degrader of BCL-2 and BCL-xL

Digant Nayak, Dongwen Lv, Yaxia Yuan, Peiyi Zhang, Wanyi Hu, Anindita Nayak, Eliza A. Ruben, Zongyang Lv, Patrick Sung, Robert Hromas, Guangrong Zheng (), Daohong Zhou () and Shaun K. Olsen ()
Additional contact information
Digant Nayak: University of Texas Health Science Center at San Antonio
Dongwen Lv: University of Texas Health Science Center at San Antonio
Yaxia Yuan: University of Texas Health Science Center at San Antonio
Peiyi Zhang: University of Florida
Wanyi Hu: University of Florida
Anindita Nayak: University of Texas Health Science Center at San Antonio
Eliza A. Ruben: University of Texas Health Science Center at San Antonio
Zongyang Lv: University of Texas Health Science Center at San Antonio
Patrick Sung: University of Texas Health Science Center at San Antonio
Robert Hromas: University of Texas Health Science Center at San Antonio
Guangrong Zheng: University of Florida
Daohong Zhou: University of Texas Health Science Center at San Antonio
Shaun K. Olsen: University of Texas Health Science Center at San Antonio

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: 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.

Date: 2024
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-024-46922-4 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-46922-4

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-024-46922-4

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().