IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v15y2024i1d10.1038_s41467-024-46922-4.html
   My bibliography  Save this article

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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-024-46922-4
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-024-46922-4?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    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.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Fengchao Yu & Guo Ci Teo & Andy T. Kong & Klemens Fröhlich & Ginny Xiaohe Li & Vadim Demichev & Alexey I. Nesvizhskii, 2023. "Analysis of DIA proteomics data using MSFragger-DIA and FragPipe computational platform," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    2. Masaji Sakaguchi & Shota Okagawa & Yuma Okubo & Yuri Otsuka & Kazuki Fukuda & Motoyuki Igata & Tatsuya Kondo & Yoshifumi Sato & Tatsuya Yoshizawa & Takaichi Fukuda & Kazuya Yamagata & Weikang Cai & Yu, 2022. "Phosphatase protector alpha4 (α4) is involved in adipocyte maintenance and mitochondrial homeostasis through regulation of insulin signaling," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    3. Ray Sajulga & Caleb Easterly & Michael Riffle & Bart Mesuere & Thilo Muth & Subina Mehta & Praveen Kumar & James Johnson & Bjoern Andreas Gruening & Henning Schiebenhoefer & Carolin A Kolmeder & Steph, 2020. "Survey of metaproteomics software tools for functional microbiome analysis," PLOS ONE, Public Library of Science, vol. 15(11), pages 1-20, November.
    4. Zhi Huang & Gennifer E. Merrihew & Eric B. Larson & Jea Park & Deanna Plubell & Edward J. Fox & Kathleen S. Montine & Caitlin S. Latimer & C. Dirk Keene & James Y. Zou & Michael J. MacCoss & Thomas J., 2023. "Brain proteomic analysis implicates actin filament processes and injury response in resilience to Alzheimer’s disease," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    5. Harim I. Won & Samuel Zinga & Olga Kandror & Tatos Akopian & Ian D. Wolf & Jessica T. P. Schweber & Ernst W. Schmid & Michael C. Chao & Maya Waldor & Eric J. Rubin & Junhao Zhu, 2024. "Targeted protein degradation in mycobacteria uncovers antibacterial effects and potentiates antibiotic efficacy," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    6. Marziah Hashimi & T. Andrew Sebrell & Jodi F. Hedges & Deann Snyder & Katrina N. Lyon & Stephanie D. Byrum & Samuel G. Mackintosh & Dan Crowley & Michelle D. Cherne & David Skwarchuk & Amanda Robison , 2023. "Antiviral responses in a Jamaican fruit bat intestinal organoid model of SARS-CoV-2 infection," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    7. Rafaela Muniz de Queiroz & Gizem Efe & Asja Guzman & Naoko Hashimoto & Yusuke Kawashima & Tomoaki Tanaka & Anil K. Rustgi & Carol Prives, 2024. "Mdm2 requires Sprouty4 to regulate focal adhesion formation and metastasis independent of p53," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    8. Daniel C. Scott & Suresh Dharuman & Elizabeth Griffith & Sergio C. Chai & Jarrid Ronnebaum & Moeko T. King & Rajendra Tangallapally & Chan Lee & Clifford T. Gee & Lei Yang & Yong Li & Victoria C. Loud, 2024. "Principles of paralog-specific targeted protein degradation engaging the C-degron E3 KLHDC2," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    9. Klemens Fröhlich & Eva Brombacher & Matthias Fahrner & Daniel Vogele & Lucas Kook & Niko Pinter & Peter Bronsert & Sylvia Timme-Bronsert & Alexander Schmidt & Katja Bärenfaller & Clemens Kreutz & Oliv, 2022. "Benchmarking of analysis strategies for data-independent acquisition proteomics using a large-scale dataset comprising inter-patient heterogeneity," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    10. Ryan P. Wurz & Huan Rui & Ken Dellamaggiore & Sudipa Ghimire-Rijal & Kaylee Choi & Kate Smither & Albert Amegadzie & Ning Chen & Xiaofen Li & Abhisek Banerjee & Qing Chen & Dane Mohl & Amit Vaish, 2023. "Affinity and cooperativity modulate ternary complex formation to drive targeted protein degradation," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    11. Di Wu & Haomin Li & Mingwei Liu & Jun Qin & Yi Sun, 2022. "The Ube2m-Rbx1 neddylation-Cullin-RING-Ligase proteins are essential for the maintenance of Regulatory T cell fitness," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    12. Valdemaras Petrosius & Pedro Aragon-Fernandez & Nil Üresin & Gergo Kovacs & Teeradon Phlairaharn & Benjamin Furtwängler & Jeff Op De Beeck & Sarah L. Skovbakke & Steffen Goletz & Simon Francis Thomsen, 2023. "Exploration of cell state heterogeneity using single-cell proteomics through sensitivity-tailored data-independent acquisition," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    13. 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.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-46922-4. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.