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Development of a BCL-xL and BCL-2 dual degrader with improved anti-leukemic activity

Author

Listed:
  • Dongwen Lv

    (College of Pharmacy, University of Florida)

  • Pratik Pal

    (College of Pharmacy, University of Florida)

  • Xingui Liu

    (College of Pharmacy, University of Florida)

  • Yannan Jia

    (University of Texas M.D. Anderson Cancer Center)

  • Dinesh Thummuri

    (College of Pharmacy, University of Florida)

  • Peiyi Zhang

    (College of Pharmacy, University of Florida)

  • Wanyi Hu

    (College of Pharmacy, University of Florida)

  • Jing Pei

    (College of Pharmacy, University of Florida)

  • Qi Zhang

    (University of Texas M.D. Anderson Cancer Center)

  • Shuo Zhou

    (College of Pharmacy, University of Florida)

  • Sajid Khan

    (College of Pharmacy, University of Florida)

  • Xuan Zhang

    (College of Pharmacy, University of Florida)

  • Nan Hua

    (College of Pharmacy, University of Florida)

  • Qingping Yang

    (College of Pharmacy, University of Florida)

  • Sebastian Arango

    (College of Pharmacy, University of Florida)

  • Weizhou Zhang

    (Immunology and Laboratory Medicine, College of Medicine, University of Florida)

  • Digant Nayak

    (Long School of Medicine, University of Texas Health Science Center at San Antonio
    Mays Cancer Center, the Long School of Medicine, University of Texas Health Science Center at San Antonio)

  • Shaun K. Olsen

    (Long School of Medicine, University of Texas Health Science Center at San Antonio
    Mays Cancer Center, the Long School of Medicine, University of Texas Health Science Center at San Antonio)

  • Susan T. Weintraub

    (Long School of Medicine, University of Texas Health Science Center at San Antonio)

  • Robert Hromas

    (Mays Cancer Center, the Long School of Medicine, University of Texas Health Science Center at San Antonio)

  • Marina Konopleva

    (University of Texas M.D. Anderson Cancer Center)

  • Yaxia Yuan

    (College of Pharmacy, University of Florida)

  • Guangrong Zheng

    (College of Pharmacy, University of Florida)

  • Daohong Zhou

    (College of Pharmacy, University of Florida)

Abstract

PROteolysis-TArgeting Chimeras (PROTACs) have emerged as an innovative drug development platform. However, most PROTACs have been generated empirically because many determinants of PROTAC specificity and activity remain elusive. Through computational modelling of the entire NEDD8-VHL Cullin RING E3 ubiquitin ligase (CRLVHL)/PROTAC/BCL-xL/UbcH5B(E2)-Ub/RBX1 complex, we find that this complex can only ubiquitinate the lysines in a defined band region on BCL-xL. Using this approach to guide our development of a series of ABT263-derived and VHL-recruiting PROTACs, we generate a potent BCL-xL and BCL-2 (BCL-xL/2) dual degrader with significantly improved antitumor activity against BCL-xL/2-dependent leukemia cells. Our results provide experimental evidence that the accessibility of lysines on a target protein plays an important role in determining the selectivity and potency of a PROTAC in inducing protein degradation, which may serve as a conceptual framework to guide the future development of PROTACs.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-27210-x
    DOI: 10.1038/s41467-021-27210-x
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    References listed on IDEAS

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    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. András Kotschy & Zoltán Szlavik & James Murray & James Davidson & Ana Leticia Maragno & Gaëtane Le Toumelin-Braizat & Maïa Chanrion & Gemma L. Kelly & Jia-Nan Gong & Donia M. Moujalled & Alain Bruno &, 2016. "The MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models," Nature, Nature, vol. 538(7626), pages 477-482, October.
    3. Georg Petzold & Eric S. Fischer & Nicolas H. Thomä, 2016. "Structural basis of lenalidomide-induced CK1α degradation by the CRL4CRBN ubiquitin ligase," Nature, Nature, vol. 532(7597), pages 127-130, April.
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    Cited by:

    1. 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.
    2. 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.
    3. 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.

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