Block a phosphatase to shut down kinase signaling

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Sci. Signal.  12 Jul 2016:
Vol. 9, Issue 436, pp. ec161
DOI: 10.1126/scisignal.aah5211

The protein tyrosine phosphatase (PTP) SHP2 mediates intracellular transduction of growth factor receptor signaling. Activating mutations in SHP2 are found in various cancers. However, unlike for kinases, targeting the catalytic site in PTPs is challenging. Chen et al. discovered an allosteric small-molecule SHP2 inhibitor that may suppress the growth of some tumors. Screening a short hairpin RNA (shRNA) library in a large panel of cancer cell lines supported previous findings that cancer cells that depend on receptor tyrosine kinases (RTKs) for survival and proliferation also depend on SHP2. Screening for SHP2 allosteric inhibitors identified SHP836, which was further optimized to SHP099. Crystal structure analysis revealed that SHP099 simultaneously binds the N- and C-terminal SH2 (phosphotyrosine binding) domains and the catalytic (phosphatase) domain, thereby locking SHP2 in an inactive conformation that can neither recognize nor dephosphorylate its substrates. SHP099 decreased the activation of extracellular signal-regulated kinase (ERK) and proliferation in various RTK-dependent cancer cell lines in culture and tumor growth in xenografts; these effects were blocked by expression of an inhibitor-resistant SHP2 mutant. The effects of SHP099 were similar to those of erlotinib, a kinase inhibitor of epidermal growth factor receptor.SHP099 is not only a useful experimental tool but may also represent a new therapeutic for use in patients with growth factor receptor-driven tumors.

Y.-N. P. Chen, M. J. LaMarche, H. M. Chan, P. Fekkes, J. Garcia-Fortanet, M. G. Acker, B. Antonakos, C. H. Chen, Z. Chen, V. G. Cooke, J. R. Dobson, Z. Deng, F. Fei, B. Firestone, M. Fodor, C. Fridrich, H. Gao, D. Grunenfelder, H. X. Hao, J. Jacob, S. Ho, K. Hsiao, Z. B. Kang, R. Karki, M. Kato, J. Larrow, L. R. La Bonte, F. Lenoir, G. Liu, S. Liu, D. Majumdar, M. J. Meyer, M. Palermo, L. Perez, M. Pu, E. Price, C. Quinn, S. Shakya, M. D. Shultz, J. Slisz, K. Venkatesan, P. Wang, M. Warmuth, S. Williams, G. Yang, J. Yuan, J. H. Zhang, P. Zhu, T. Ramsey, N. J. Keen, W. R. Sellers, T. Stams, P. D. Fortin, Allosteric inhibition of SHP2 phosphatase inhibits cancers driven by receptor tyrosine kinases. Nature 535, 148–152 (2016). [PubMed]