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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


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.


  1. 1.

    , , & The tyrosine phosphatase Shp2 in development and cancer. Adv. Cancer Res. 106, 53–89 (2010)

  2. 2.

    & PTPN11 is the first identified proto-oncogene that encodes a tyrosine phosphatase. Blood 109, 862–867 (2007)

  3. 3.

    , , , & Protein tyrosine phosphatase SHP-2: a proto-oncogene product that promotes Ras activation. Cancer Sci. 100, 1786–1793 (2009)

  4. 4.

    & The role of Shp2 (PTPN11) in cancer. Curr. Opin. Genet. Dev. 17, 23–30 (2007)

  5. 5.

    , & Protein-tyrosine phosphatases and cancer. Nat. Rev. Cancer 6, 307–320 (2006)

  6. 6.

    , , , & Characterization of phosphotyrosine binding motifs in the cytoplasmic domain of B and T lymphocyte attenuator required for association with protein tyrosine phosphatases SHP-1 and SHP-2. Biochem. Biophys. Res. Commun. 312, 1236–1243 (2003)

  7. 7.

    , , , & A rheostat for immune responses: the unique properties of PD-1 and their advantages for clinical application. Nat. Immunol. 14, 1212–1218 (2013)

  8. 8.

    et al. PTPN11 is a central node in intrinsic and acquired resistance to targeted cancer drugs. Cell Reports 12, 1978–1985 (2015)

  9. 9.

    et al. Inhibition of Shp2 suppresses mutant EGFR-induced lung tumors in transgenic mouse model of lung adenocarcinoma. Oncotarget 6, 6191–6202 (2015)

  10. 10.

    et al. The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity. Nature 483, 603–607 (2012)

  11. 11.

    et al. Shp2 protein tyrosine phosphatase inhibitor activity of estramustine phosphate and its triterpenoid analogs. Bioorg. Med. Chem. Lett. 21, 730–733 (2011)

  12. 12.

    et al. Selective inhibitors of the protein tyrosine phosphatase SHP2 block cellular motility and growth of cancer cells in vitro and in vivo. ChemMedChem 10, 815–826 (2015)

  13. 13.

    et al. Exploring the existing drug space for novel pTyr mimetic and SHP2 inhibitors. ACS Med. Chem. Lett. 6, 782–786 (2015)

  14. 14.

    et al. Specific inhibitors of the protein tyrosine phosphatase Shp2 identified by high-throughput docking. Proc. Natl Acad. Sci. USA 105, 7275–7280 (2008)

  15. 15.

    et al. Therapeutic potential of targeting the oncogenic SHP2 phosphatase. J. Med. Chem. 57, 6594–6609 (2014)

  16. 16.

    , , & Potent stimulation of SH-PTP2 phosphatase activity by simultaneous occupancy of both SH2 domains. J. Biol. Chem. 270, 2897–2900 (1995)

  17. 17.

    , , , & Crystal structure of the tyrosine phosphatase SHP-2. Cell 92, 441–450 (1998)

  18. 18.

    et al. Extended kinase profile and properties of the protein kinase inhibitor nilotinib. Biochim. Biophys. Acta. 1804, 445–453 (2010)

  19. 19.

    et al. Analysis of pharmacology data and the prediction of adverse drug reactions and off-target effects from chemical structure. ChemMedChem 2, 861–873 (2007)

  20. 20.

    et al. Discovery of a potent, selective protein tyrosine phosphatase 1B inhibitor using a linked-fragment strategy. J. Am. Chem. Soc. 125, 4087–4096 (2003)

  21. 21.

    et al. Allosteric Wip1 phosphatase inhibition through flap-subdomain interaction. Nat. Chem. Biol. 10, 181–187 (2014)

  22. 22.

    et al. Functional epigenetics approach identifies BRM/SMARCA2 as a critical synthetic lethal target in BRG1-deficient cancers. Proc. Natl Acad. Sci. USA 111, 3128–3133 (2014)

  23. 23.

    et al. ATARiS: computational quantification of gene suppression phenotypes from multisample RNAi screens. Genome Res. 23, 665–678 (2013)

  24. 24.

    , , & Voltage-gated sodium channels as therapeutic targets. Drug Discov. Today 5, 506–520 (2000)

  25. 25.

    et al. Isoxazole carboxylic acids as protein tyrosine phosphatase 1B (PTP1B) inhibitors. Bioorg. Med. Chem. Lett. 14, 5543–5546 (2004)

  26. 26.

    Acta Crystallogr. D 66, 125–132 (2010)

  27. 27.

    et al. BUSTER version 2.8.0. (Global Phasing Ltd., 2009)

  28. 28.

    , , & Features and development of Coot. Acta Crystallogr. D 66, 486–501 (2010)

  29. 29.

    et al. Inhibition of wild-type p53-expressing AML by the novel small molecule HDM2 inhibitor CGM097. Mol. Cancer Ther. 14, 2249–2259 (2015)

Download references


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


  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


  1. Search for Ying-Nan P. Chen in:

  2. Search for Matthew J. LaMarche in:

  3. Search for Ho Man Chan in:

  4. Search for Peter Fekkes in:

  5. Search for Jorge Garcia-Fortanet in:

  6. Search for Michael G. Acker in:

  7. Search for Brandon Antonakos in:

  8. Search for Christine Hiu-Tung Chen in:

  9. Search for Zhouliang Chen in:

  10. Search for Vesselina G. Cooke in:

  11. Search for Jason R. Dobson in:

  12. Search for Zhan Deng in:

  13. Search for Feng Fei in:

  14. Search for Brant Firestone in:

  15. Search for Michelle Fodor in:

  16. Search for Cary Fridrich in:

  17. Search for Hui Gao in:

  18. Search for Denise Grunenfelder in:

  19. Search for Huai-Xiang Hao in:

  20. Search for Jaison Jacob in:

  21. Search for Samuel Ho in:

  22. Search for Kathy Hsiao in:

  23. Search for Zhao B. Kang in:

  24. Search for Rajesh Karki in:

  25. Search for Mitsunori Kato in:

  26. Search for Jay Larrow in:

  27. Search for Laura R. La Bonte in:

  28. Search for Francois Lenoir in:

  29. Search for Gang Liu in:

  30. Search for Shumei Liu in:

  31. Search for Dyuti Majumdar in:

  32. Search for Matthew J. Meyer in:

  33. Search for Mark Palermo in:

  34. Search for Lawrence Perez in:

  35. Search for Minying Pu in:

  36. Search for Edmund Price in:

  37. Search for Christopher Quinn in:

  38. Search for Subarna Shakya in:

  39. Search for Michael D. Shultz in:

  40. Search for Joanna Slisz in:

  41. Search for Kavitha Venkatesan in:

  42. Search for Ping Wang in:

  43. Search for Markus Warmuth in:

  44. Search for Sarah Williams in:

  45. Search for Guizhi Yang in:

  46. Search for Jing Yuan in:

  47. Search for Ji-Hu Zhang in:

  48. Search for Ping Zhu in:

  49. Search for Timothy Ramsey in:

  50. Search for Nicholas J. Keen in:

  51. Search for William R. Sellers in:

  52. Search for Travis Stams in:

  53. Search for Pascal D. Fortin in:


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.

About this article

Publication history






Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.