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Selective inhibition of leukemia-associated SHP2E69K mutant by the allosteric SHP2 inhibitor SHP099

Leukemia volume 32, pages 1246–1249 (2018)Cite this article

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SHP2 (PTPN11) is a protein tyrosine phosphatase (PTP) containing two Src homology-2 domains (N-SH2, C-SH2), a PTP domain, and a carboxyl-terminal region [1]. SHP2 is auto-inhibited by the N-SH2 domain and PTP domain interaction in the basal state. In cancer cells, SHP2 is activated by oncogenic protein tyrosine kinases (PTKs) or gain-of-function (GOF) mutations. GOF SHP2 mutations also link to Noonan Syndrome (NS) [2].

SHP2 plays important roles in tumor growth [3, 4], in oncogenesis driven by PTK oncogenes such as FLT3-ITD in acute myeloid leukemia [5], and in immune checkpoints mediated by PD-1 or BTLA [6]. GOF SHP2 mutations are found in leukemias, particularly juvenile myelomonocytic leukemia (JMML), and in solid tumors [1].

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Acknowledgements

This study was supported by National Institutes of Health (NIH) grant R01CA17456 (to J. Wu), and by the Chemical Biology Core facilities at the H. Lee Moffitt Cancer Center supported by NIH grant P30CA076292, and the shared resources at the University of Oklahoma Health Sciences Center supported by NIH grant P20GM103639.

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Authors and Affiliations

  1. Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

    X Sun & J Wu

  2. Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA

    Y Ren, Z Chen & J Wu

  3. Department of Drug Discovery, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA

    S Gunawan, HR Lawrence & NJ Lawrence

  4. Department of Chemistry, University of South Florida, Tampa, FL, USA

    P Teng & J Cai

  5. Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

    J Wu

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Correspondence to J Wu.

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Sun, X., Ren, Y., Gunawan, S. et al. Selective inhibition of leukemia-associated SHP2E69K mutant by the allosteric SHP2 inhibitor SHP099. Leukemia 32, 1246–1249 (2018). https://doi.org/10.1038/s41375-018-0020-5

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