Abstract

The non-receptor protein tyrosine phosphatase SHP2, encoded by PTPN11, has an important role in signal transduction downstream of growth factor receptor signalling and was the first reported oncogenic tyrosine phosphatase1. Activating mutations of SHP2 have been associated with developmental pathologies such as Noonan syndrome and are found in multiple cancer types, including leukaemia, lung and breast cancer and neuroblastoma1,2,3,4,5. SHP2 is ubiquitously expressed and regulates cell survival and proliferation primarily through activation of the RAS–ERK signalling pathway2,3. It is also a key mediator of the programmed cell death 1 (PD-1) and B- and T-lymphocyte attenuator (BTLA) immune checkpoint pathways6,7. Reduction of SHP2 activity suppresses tumour cell growth and is a potential target of cancer therapy8,9. Here we report the discovery of a highly potent (IC50 = 0.071 μM), selective and orally bioavailable small-molecule SHP2 inhibitor, SHP099, that stabilizes SHP2 in an auto-inhibited conformation. SHP099 concurrently binds to the interface of the N-terminal SH2, C-terminal SH2, and protein tyrosine phosphatase domains, thus inhibiting SHP2 activity through an allosteric mechanism. SHP099 suppresses RAS–ERK signalling to inhibit the proliferation of receptor-tyrosine-kinase-driven human cancer cells in vitro and is efficacious in mouse tumour xenograft models. Together, these data demonstrate that pharmacological inhibition of SHP2 is a valid therapeutic approach for the treatment of cancers.

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Accessions

Primary accessions

Protein Data Bank

Data deposits

Atomic coordinates and structure factors for the SHP2–SHP099 binary complex structure have been deposited with the Protein Data Bank under accession number 5EHR.

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Acknowledgements

Use of the IMCA-CAT beamline 17-ID at the Advanced Photon Source was supported by the companies of the Industrial Macromolecular Crystallography Association through a contract with Hauptman-Woodward Medical Research Institute. Use of the Advanced Photon Source was supported by the US Department of Energy, Office of Science, Office of Basic Energy Sciences, under contract number DE-AC02-06CH11357.

Author information

Affiliations

  1. Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA

    • 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
    • , Jason R. Dobson
    • , Zhan Deng
    • , Feng Fei
    • , Brant Firestone
    • , Michelle Fodor
    • , Cary Fridrich
    • , Hui Gao
    • , Denise Grunenfelder
    • , Huai-Xiang Hao
    • , Jaison Jacob
    • , Samuel Ho
    • , Kathy Hsiao
    • , Zhao B. Kang
    • , Rajesh Karki
    • , Mitsunori Kato
    • , Jay Larrow
    • , Laura R. La Bonte
    • , Francois Lenoir
    • , Gang Liu
    • , Shumei Liu
    • , Dyuti Majumdar
    • , Matthew J. Meyer
    • , Mark Palermo
    • , Lawrence Perez
    • , Minying Pu
    • , Edmund Price
    • , Christopher Quinn
    • , Subarna Shakya
    • , Michael D. Shultz
    • , Joanna Slisz
    • , Kavitha Venkatesan
    • , Ping Wang
    • , Markus Warmuth
    • , Sarah Williams
    • , Guizhi Yang
    • , Jing Yuan
    • , Ji-Hu Zhang
    • , Ping Zhu
    • , Timothy Ramsey
    • , Nicholas J. Keen
    • , William R. Sellers
    • , Travis Stams
    •  & Pascal D. Fortin

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Contributions

Y.P.C., F.F., H.-X.H., K.H., S.L., J.S., P.Z., H.M.C. performed or directed cellular assays data generation and analysis; P.F., M.G.A., Z.B.K., S.H., E.P., C.Q., S.S, P.W., J.-H.Z. and P.D.F. performed or directed biochemical experiments; B.A., V.G.C., B.F., H.G., L.R.L.B., M.J.M., M.P., G.Y. and J.Y. performed or directed in vivo pharmacology or pharmacokinetic/pharmacodynamics experiments and data analysis; J.R.D. and K.V. directed or performed bioinformatics analyses; M.J.L., J.G.-F., C.F., C.H.-T.C, Z.C., D.G., R.K., M.K., J.L., F.L., G.L., D.M., M.P., L.P., M.D.S., T.S., S.W. Designed, synthesized and/or directed the design or synthesis of SHP2 inhibitors; Z.D., M.K., and S.W. performed protein and inhibitor structural modelling or cheminformatics analyses; M.F., J.J. and T.S. designed, directed or performed biophysics experiments; M.F. and T.S. directed or performed x-ray crystallography experiments; Y.P.C., J.R.D., L.R.L.B., M.F., M.J.M., K.V., H.M.C., T.S., W.R.S. and P.D.F. prepared figures and tables for the main text and Supplementary Information; Y.P.C., M.J.L., J.R.D., L.R.L.B., M.J.M., K.V., N.J.K., H.M.C., T.S., W.R.S. and P.D.F. wrote and edited the main text and Supplementary Information; P.D.F., N.J.K., T.R., T.S., W.R.S. and M.W. contributed to overall project oversight.

Competing interests

All authors performed the work herein as employees of the Novartis Institutes for Biomedical Research, Inc.

Corresponding authors

Correspondence to William R. Sellers or Travis Stams or Pascal D. Fortin.

Reviewer Information Nature thanks B. Neel and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Extended data

Supplementary information

PDF files

  1. 1.

    Supplementary Figure 1

    This file contains the raw data for Figure 3e and Extended Data Figures 1a-d, 2a, 4a and 5a.

Excel files

  1. 1.

    Supplementary Table 1

    This file shows the SHP099 inhibitory activity against hematopoietic cell lines. Data used to generate Figure 3b.

  2. 2.

    Supplementary Table 2

    This file shows the Inhibition of colorectal cancer cell lines proliferation by SHP099 or Lapatinib. Data used to generate extended data figure 4d.

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DOI

https://doi.org/10.1038/nature18621

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