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An inhibitor of NEDD8-activating enzyme as a new approach to treat cancer

Author

Listed:
  • Teresa A. Soucy

    (Discovery, Millennium Pharmaceuticals, Inc., 40 Landsdowne Street, Cambridge, Massachusetts 02139, USA)

  • Peter G. Smith

    (Discovery, Millennium Pharmaceuticals, Inc., 40 Landsdowne Street, Cambridge, Massachusetts 02139, USA)

  • Michael A. Milhollen

    (Discovery, Millennium Pharmaceuticals, Inc., 40 Landsdowne Street, Cambridge, Massachusetts 02139, USA)

  • Allison J. Berger

    (Discovery, Millennium Pharmaceuticals, Inc., 40 Landsdowne Street, Cambridge, Massachusetts 02139, USA)

  • James M. Gavin

    (Discovery, Millennium Pharmaceuticals, Inc., 40 Landsdowne Street, Cambridge, Massachusetts 02139, USA)

  • Sharmila Adhikari

    (Discovery, Millennium Pharmaceuticals, Inc., 40 Landsdowne Street, Cambridge, Massachusetts 02139, USA)

  • James E. Brownell

    (Discovery, Millennium Pharmaceuticals, Inc., 40 Landsdowne Street, Cambridge, Massachusetts 02139, USA)

  • Kristine E. Burke

    (Discovery, Millennium Pharmaceuticals, Inc., 40 Landsdowne Street, Cambridge, Massachusetts 02139, USA)

  • David P. Cardin

    (Discovery, Millennium Pharmaceuticals, Inc., 40 Landsdowne Street, Cambridge, Massachusetts 02139, USA)

  • Stephen Critchley

    (Discovery, Millennium Pharmaceuticals, Inc., 40 Landsdowne Street, Cambridge, Massachusetts 02139, USA)

  • Courtney A. Cullis

    (Discovery, Millennium Pharmaceuticals, Inc., 40 Landsdowne Street, Cambridge, Massachusetts 02139, USA)

  • Amanda Doucette

    (Discovery, Millennium Pharmaceuticals, Inc., 40 Landsdowne Street, Cambridge, Massachusetts 02139, USA)

  • James J. Garnsey

    (Discovery, Millennium Pharmaceuticals, Inc., 40 Landsdowne Street, Cambridge, Massachusetts 02139, USA)

  • Jeffrey L. Gaulin

    (Discovery, Millennium Pharmaceuticals, Inc., 40 Landsdowne Street, Cambridge, Massachusetts 02139, USA)

  • Rachel E. Gershman

    (Discovery, Millennium Pharmaceuticals, Inc., 40 Landsdowne Street, Cambridge, Massachusetts 02139, USA)

  • Anna R. Lublinsky

    (Discovery, Millennium Pharmaceuticals, Inc., 40 Landsdowne Street, Cambridge, Massachusetts 02139, USA)

  • Alice McDonald

    (Discovery, Millennium Pharmaceuticals, Inc., 40 Landsdowne Street, Cambridge, Massachusetts 02139, USA)

  • Hirotake Mizutani

    (Discovery, Millennium Pharmaceuticals, Inc., 40 Landsdowne Street, Cambridge, Massachusetts 02139, USA)

  • Usha Narayanan

    (Discovery, Millennium Pharmaceuticals, Inc., 40 Landsdowne Street, Cambridge, Massachusetts 02139, USA)

  • Edward J. Olhava

    (Discovery, Millennium Pharmaceuticals, Inc., 40 Landsdowne Street, Cambridge, Massachusetts 02139, USA)

  • Stephane Peluso

    (Discovery, Millennium Pharmaceuticals, Inc., 40 Landsdowne Street, Cambridge, Massachusetts 02139, USA)

  • Mansoureh Rezaei

    (Discovery, Millennium Pharmaceuticals, Inc., 40 Landsdowne Street, Cambridge, Massachusetts 02139, USA)

  • Michael D. Sintchak

    (Discovery, Millennium Pharmaceuticals, Inc., 40 Landsdowne Street, Cambridge, Massachusetts 02139, USA)

  • Tina Talreja

    (Discovery, Millennium Pharmaceuticals, Inc., 40 Landsdowne Street, Cambridge, Massachusetts 02139, USA)

  • Michael P. Thomas

    (Discovery, Millennium Pharmaceuticals, Inc., 40 Landsdowne Street, Cambridge, Massachusetts 02139, USA)

  • Tary Traore

    (Discovery, Millennium Pharmaceuticals, Inc., 40 Landsdowne Street, Cambridge, Massachusetts 02139, USA)

  • Stepan Vyskocil

    (Discovery, Millennium Pharmaceuticals, Inc., 40 Landsdowne Street, Cambridge, Massachusetts 02139, USA)

  • Gabriel S. Weatherhead

    (Discovery, Millennium Pharmaceuticals, Inc., 40 Landsdowne Street, Cambridge, Massachusetts 02139, USA)

  • Jie Yu

    (Discovery, Millennium Pharmaceuticals, Inc., 40 Landsdowne Street, Cambridge, Massachusetts 02139, USA)

  • Julie Zhang

    (Discovery, Millennium Pharmaceuticals, Inc., 40 Landsdowne Street, Cambridge, Massachusetts 02139, USA)

  • Lawrence R. Dick

    (Discovery, Millennium Pharmaceuticals, Inc., 40 Landsdowne Street, Cambridge, Massachusetts 02139, USA)

  • Christopher F. Claiborne

    (Discovery, Millennium Pharmaceuticals, Inc., 40 Landsdowne Street, Cambridge, Massachusetts 02139, USA)

  • Mark Rolfe

    (Discovery, Millennium Pharmaceuticals, Inc., 40 Landsdowne Street, Cambridge, Massachusetts 02139, USA)

  • Joseph B. Bolen

    (Discovery, Millennium Pharmaceuticals, Inc., 40 Landsdowne Street, Cambridge, Massachusetts 02139, USA)

  • Steven P. Langston

    (Discovery, Millennium Pharmaceuticals, Inc., 40 Landsdowne Street, Cambridge, Massachusetts 02139, USA)

Abstract

The clinical development of an inhibitor of cellular proteasome function suggests that compounds targeting other components of the ubiquitin–proteasome system might prove useful for the treatment of human malignancies. NEDD8-activating enzyme (NAE) is an essential component of the NEDD8 conjugation pathway that controls the activity of the cullin-RING subtype of ubiquitin ligases, thereby regulating the turnover of a subset of proteins upstream of the proteasome. Substrates of cullin-RING ligases have important roles in cellular processes associated with cancer cell growth and survival pathways. Here we describe MLN4924, a potent and selective inhibitor of NAE. MLN4924 disrupts cullin-RING ligase-mediated protein turnover leading to apoptotic death in human tumour cells by a new mechanism of action, the deregulation of S-phase DNA synthesis. MLN4924 suppressed the growth of human tumour xenografts in mice at compound exposures that were well tolerated. Our data suggest that NAE inhibitors may hold promise for the treatment of cancer.

Suggested Citation

  • Teresa A. Soucy & Peter G. Smith & Michael A. Milhollen & Allison J. Berger & James M. Gavin & Sharmila Adhikari & James E. Brownell & Kristine E. Burke & David P. Cardin & Stephen Critchley & Courtne, 2009. "An inhibitor of NEDD8-activating enzyme as a new approach to treat cancer," Nature, Nature, vol. 458(7239), pages 732-736, April.
    • Handle: RePEc:nat:nature:v:458:y:2009:i:7239:d:10.1038_nature07884
    DOI: 10.1038/nature07884
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    Cited by:

    1. Daewon Lee & Eunju Yoon & Su Jin Ham & Kunwoo Lee & Hansaem Jang & Daihn Woo & Da Hyun Lee & Sehyeon Kim & Sekyu Choi & Jongkyeong Chung, 2024. "Diabetic sensory neuropathy and insulin resistance are induced by loss of UCHL1 in Drosophila," Nature Communications, Nature, vol. 15(1), pages 1-22, December.
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    3. Cheng Xu & Hongyi Zhou & Yulan Jin & Khushboo Sahay & Anna Robicsek & Yisong Liu & Kunzhe Dong & Jiliang Zhou & Amanda Barrett & Huabo Su & Weiqin Chen, 2022. "Hepatic neddylation deficiency triggers fatal liver injury via inducing NF-κB-inducing kinase in mice," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    4. 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.
    5. Yongchang Zhu & Xiping Zhang & Meng Gao & Yanchao Huang & Yuanqing Tan & Avital Parnas & Sizhong Wu & Delin Zhan & Sheera Adar & Jinchuan Hu, 2024. "Coordination of transcription-coupled repair and repair-independent release of lesion-stalled RNA polymerase II," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    6. Debasish Paul & Stephen C. Kales & James A. Cornwell & Marwa M. Afifi & Ganesha Rai & Alexey Zakharov & Anton Simeonov & Steven D. Cappell, 2022. "Revealing β-TrCP activity dynamics in live cells with a genetically encoded biosensor," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    7. Irineos Papakyriacou & Ginte Kutkaite & Marta Rúbies Bedós & Divya Nagarajan & Liam P. Alford & Michael P. Menden & Yumeng Mao, 2024. "Loss of NEDD8 in cancer cells causes vulnerability to immune checkpoint blockade in triple-negative breast cancer," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    8. María Arroyo & Florian D. Hastert & Andreas Zhadan & Florian Schelter & Susanne Zimbelmann & Cathia Rausch & Anne K. Ludwig & Thomas Carell & M. Cristina Cardoso, 2022. "Isoform-specific and ubiquitination dependent recruitment of Tet1 to replicating heterochromatin modulates methylcytosine oxidation," Nature Communications, Nature, vol. 13(1), pages 1-28, December.
    9. Gang Xue & Jianing Xie & Matthias Hinterndorfer & Marko Cigler & Lara Dötsch & Hana Imrichova & Philipp Lampe & Xiufen Cheng & Soheila Rezaei Adariani & Georg E. Winter & Herbert Waldmann, 2023. "Discovery of a Drug-like, Natural Product-Inspired DCAF11 Ligand Chemotype," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    10. Yilun Sun & Simone A. Baechler & Xiaohu Zhang & Suresh Kumar & Valentina M. Factor & Yasuhiro Arakawa & Cindy H. Chau & Kanako Okamoto & Anup Parikh & Bob Walker & Yijun P. Su & Jiji Chen & Tabitha Ti, 2023. "Targeting neddylation sensitizes colorectal cancer to topoisomerase I inhibitors by inactivating the DCAF13-CRL4 ubiquitin ligase complex," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    11. Jiajun Tan & Yingfeng Li & Xiang Li & Xiaoxiao Zhu & Liping Liu & Hua Huang & Jiahua Wei & Hailing Wang & Yong Tian & Zhigao Wang & Zhuqiang Zhang & Bing Zhu, 2024. "Pramel15 facilitates zygotic nuclear DNMT1 degradation and DNA demethylation," Nature Communications, Nature, vol. 15(1), pages 1-17, December.

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