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

Author

Listed:
  • 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)

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.

Suggested Citation

  • 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 & Shaun K. Olsen, 2024. "Development and crystal structures of a potent second-generation dual degrader of BCL-2 and BCL-xL," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-46922-4
    DOI: 10.1038/s41467-024-46922-4
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    References listed on IDEAS

    as
    1. Blake E. Smith & Stephen L. Wang & Saul Jaime-Figueroa & Alicia Harbin & Jing Wang & Brian D. Hamman & Craig M. Crews, 2019. "Differential PROTAC substrate specificity dictated by orientation of recruited E3 ligase," Nature Communications, Nature, vol. 10(1), pages 1-13, December.
    2. Dongwen Lv & Pratik Pal & Xingui Liu & Yannan Jia & Dinesh Thummuri & Peiyi Zhang & Wanyi Hu & Jing Pei & Qi Zhang & Shuo Zhou & Sajid Khan & Xuan Zhang & Nan Hua & Qingping Yang & Sebastian Arango & , 2021. "Development of a BCL-xL and BCL-2 dual degrader with improved anti-leukemic activity," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    3. Brian C. Searle & Lindsay K. Pino & Jarrett D. Egertson & Ying S. Ting & Robert T. Lawrence & Brendan X. MacLean & Judit Villén & Michael J. MacCoss, 2018. "Chromatogram libraries improve peptide detection and quantification by data independent acquisition mass spectrometry," Nature Communications, Nature, vol. 9(1), pages 1-12, December.
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