2. Academic Validation
  3. Development and crystal structures of a potent second-generation dual degrader of BCL-2 and BCL-xL

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

  • Nat Commun. 2024 Mar 29;15(1):2743. doi: 10.1038/s41467-024-46922-4.
Digant Nayak # 1,  Dongwen Lv # 1,  Yaxia Yuan 1,  Peiyi Zhang 2,  Wanyi Hu 2,  Anindita Nayak 1,  Eliza A Ruben 1,  Zongyang Lv 1,  Patrick Sung 1,  Robert Hromas 3,  Guangrong Zheng 4,  Daohong Zhou 5,  Shaun K Olsen 6
Affiliations

Affiliations

  • 1 Department 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.
  • 2 Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL, 32610, USA.
  • 3 Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA.
  • 4 Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL, 32610, USA. zhengg@cop.ufl.edu.
  • 5 Department 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. zhoud@uthscsa.edu.
  • 6 Department 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. olsens@uthscsa.edu.
  • # Contributed equally.
PMID: 38548768 DOI: 10.1038/s41467-024-46922-4
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.

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