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Allosteric inhibition of SHP2 phosphatase inhibits cancers driven by receptor tyrosine kinases

Author

Listed:
  • Ying-Nan P. Chen

    (Novartis Institutes for Biomedical Research)

  • Matthew J. LaMarche

    (Novartis Institutes for Biomedical Research)

  • Ho Man Chan

    (Novartis Institutes for Biomedical Research)

  • Peter Fekkes

    (Novartis Institutes for Biomedical Research)

  • Jorge Garcia-Fortanet

    (Novartis Institutes for Biomedical Research)

  • Michael G. Acker

    (Novartis Institutes for Biomedical Research)

  • Brandon Antonakos

    (Novartis Institutes for Biomedical Research)

  • Christine Hiu-Tung Chen

    (Novartis Institutes for Biomedical Research)

  • Zhouliang Chen

    (Novartis Institutes for Biomedical Research)

  • Vesselina G. Cooke

    (Novartis Institutes for Biomedical Research)

  • Jason R. Dobson

    (Novartis Institutes for Biomedical Research)

  • Zhan Deng

    (Novartis Institutes for Biomedical Research)

  • Feng Fei

    (Novartis Institutes for Biomedical Research)

  • Brant Firestone

    (Novartis Institutes for Biomedical Research)

  • Michelle Fodor

    (Novartis Institutes for Biomedical Research)

  • Cary Fridrich

    (Novartis Institutes for Biomedical Research)

  • Hui Gao

    (Novartis Institutes for Biomedical Research)

  • Denise Grunenfelder

    (Novartis Institutes for Biomedical Research)

  • Huai-Xiang Hao

    (Novartis Institutes for Biomedical Research)

  • Jaison Jacob

    (Novartis Institutes for Biomedical Research)

  • Samuel Ho

    (Novartis Institutes for Biomedical Research)

  • Kathy Hsiao

    (Novartis Institutes for Biomedical Research)

  • Zhao B. Kang

    (Novartis Institutes for Biomedical Research)

  • Rajesh Karki

    (Novartis Institutes for Biomedical Research)

  • Mitsunori Kato

    (Novartis Institutes for Biomedical Research)

  • Jay Larrow

    (Novartis Institutes for Biomedical Research)

  • Laura R. La Bonte

    (Novartis Institutes for Biomedical Research)

  • Francois Lenoir

    (Novartis Institutes for Biomedical Research)

  • Gang Liu

    (Novartis Institutes for Biomedical Research)

  • Shumei Liu

    (Novartis Institutes for Biomedical Research)

  • Dyuti Majumdar

    (Novartis Institutes for Biomedical Research)

  • Matthew J. Meyer

    (Novartis Institutes for Biomedical Research)

  • Mark Palermo

    (Novartis Institutes for Biomedical Research)

  • Lawrence Perez

    (Novartis Institutes for Biomedical Research)

  • Minying Pu

    (Novartis Institutes for Biomedical Research)

  • Edmund Price

    (Novartis Institutes for Biomedical Research)

  • Christopher Quinn

    (Novartis Institutes for Biomedical Research)

  • Subarna Shakya

    (Novartis Institutes for Biomedical Research)

  • Michael D. Shultz

    (Novartis Institutes for Biomedical Research)

  • Joanna Slisz

    (Novartis Institutes for Biomedical Research)

  • Kavitha Venkatesan

    (Novartis Institutes for Biomedical Research)

  • Ping Wang

    (Novartis Institutes for Biomedical Research)

  • Markus Warmuth

    (Novartis Institutes for Biomedical Research)

  • Sarah Williams

    (Novartis Institutes for Biomedical Research)

  • Guizhi Yang

    (Novartis Institutes for Biomedical Research)

  • Jing Yuan

    (Novartis Institutes for Biomedical Research)

  • Ji-Hu Zhang

    (Novartis Institutes for Biomedical Research)

  • Ping Zhu

    (Novartis Institutes for Biomedical Research)

  • Timothy Ramsey

    (Novartis Institutes for Biomedical Research)

  • Nicholas J. Keen

    (Novartis Institutes for Biomedical Research)

  • William R. Sellers

    (Novartis Institutes for Biomedical Research)

  • Travis Stams

    (Novartis Institutes for Biomedical Research)

  • Pascal D. Fortin

    (Novartis Institutes for Biomedical Research)

Abstract

SHP099, a selective inhibitor of signalling meditator SHP2 with drug-like properties, has an allosteric mechanism of action whereby it stabilizes SHP2 in an auto-inhibited conformation, and suppresses RAS–ERK signalling and proliferation in receptor-tyrosine-kinase-driven cancer cell lines and mouse tumour xenograft models.

Suggested Citation

  • Ying-Nan P. Chen & Matthew J. LaMarche & Ho Man Chan & Peter Fekkes & Jorge Garcia-Fortanet & Michael G. Acker & Brandon Antonakos & Christine Hiu-Tung Chen & Zhouliang Chen & Vesselina G. Cooke & Jas, 2016. "Allosteric inhibition of SHP2 phosphatase inhibits cancers driven by receptor tyrosine kinases," Nature, Nature, vol. 535(7610), pages 148-152, July.
    • Handle: RePEc:nat:nature:v:535:y:2016:i:7610:d:10.1038_nature18621
    DOI: 10.1038/nature18621
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    Cited by:

    1. Fenli Shao & Qianqian Liu & Yuyu Zhu & Zhidan Fan & Wenjun Chen & Shijia Liu & Xiaohui Li & Wenjie Guo & Gen-Sheng Feng & Haiguo Yu & Qiang Xu & Yang Sun, 2021. "Targeting chondrocytes for arresting bony fusion in ankylosing spondylitis," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    2. Tanaz Sharifnia & Mathias J. Wawer & Amy Goodale & Yenarae Lee & Mariya Kazachkova & Joshua M. Dempster & Sandrine Muller & Joan Levy & Daniel M. Freed & Josh Sommer & Jérémie Kalfon & Francisca Vazqu, 2023. "Mapping the landscape of genetic dependencies in chordoma," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    3. Zhiyong Xu & Chunyi Guo & Qiaoli Ye & Yueli Shi & Yihui Sun & Jie Zhang & Jiaqi Huang & Yizhou Huang & Chunlai Zeng & Xue Zhang & Yuehai Ke & Hongqiang Cheng, 2021. "Endothelial deletion of SHP2 suppresses tumor angiogenesis and promotes vascular normalization," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    4. Takayoshi Shirasaki & Satoshi Yamagoe & Tetsuro Shimakami & Kazuhisa Murai & Ryu Imamura & Kiyo-Aki Ishii & Hiroaki Takayama & Yukako Matsumoto & Natsumi Tajima-Shirasaki & Naoto Nagata & Ryogo Shimiz, 2022. "Leukocyte cell-derived chemotaxin 2 is an antiviral regulator acting through the proto-oncogene MET," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    5. Surbhi Chouhan & Dhivya Sridaran & Cody Weimholt & Jingqin Luo & Tiandao Li & Myles C. Hodgson & Luana N. Santos & Samantha Sommer & Bin Fang & John M. Koomen & Markus Seeliger & Cheng-Kui Qu & Armell, 2024. "SHP2 as a primordial epigenetic enzyme expunges histone H3 pTyr-54 to amend androgen receptor homeostasis," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    6. Teklab Gebregiworgis & Yoshihito Kano & Jonathan St-Germain & Nikolina Radulovich & Molly L. Udaskin & Ahmet Mentes & Richard Huang & Betty P. K. Poon & Wenguang He & Ivette Valencia-Sama & Claire M. , 2021. "The Q61H mutation decouples KRAS from upstream regulation and renders cancer cells resistant to SHP2 inhibitors," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    7. Peter G. Miller & Murugappan Sathappa & Jamie A. Moroco & Wei Jiang & Yue Qian & Sumaiya Iqbal & Qi Guo & Andrew O. Giacomelli & Subrata Shaw & Camille Vernier & Besnik Bajrami & Xiaoping Yang & Ceris, 2022. "Allosteric inhibition of PPM1D serine/threonine phosphatase via an altered conformational state," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    8. Shiyun Cao & Shoukai Kang & Haibin Mao & Jiayu Yao & Liangcai Gu & Ning Zheng, 2022. "Defining molecular glues with a dual-nanobody cannabidiol sensor," Nature Communications, Nature, vol. 13(1), pages 1-14, December.

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