Browse views: by Year, by Function, by GLF, by Subfunction, by Conference, by Journal

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

Chen, Ying-Nan P and LaMarche, Matthew J and Chan, Ho Man and Fekkes, Peter and Garcia-Fortanet, Jorge and Acker, Michael G and Antonakos, Brandon and Chen, Christine Hiu-Tung and Chen, Zhouliang and Cooke, Vesselina G and Dobson, Jason R and Deng, Zhan and Fei, Feng and Firestone, Brant and Fodor, Michelle and Fridrich, Cary and Gao, Hui and Grunenfelder, Denise and Hao, Huai-Xiang and Jacob, Jaison and Ho, Samuel and Hsiao, Kathy and Kang, Zhao B and Karki, Rajesh and Kato, Mitsunori and Larrow, Jay and La Bonte, Laura R and Lenoir, Francois and Liu, Gang and Liu, Shumei and Majumdar, Dyuti and Meyer, Matthew J and Palermo, Mark and Perez, Lawrence and Pu, Minying and Price, Edmund and Quinn, Christopher and Shakya, Subarna and Shultz, Michael D and Slisz, Joanna and Venkatesan, Kavitha and Wang, Ping and Warmuth, Markus and Williams, Sarah and Yang, Guizhi and Yuan, Jing and Zhang, Ji-Hu and Zhu, Ping and Ramsey, Timothy and Keen, Nicholas J and Sellers, William R and Stams, Travis and Fortin, Pascal D (2016) Allosteric inhibition of SHP2 phosphatase inhibits cancers driven by receptor tyrosine kinases. Nature, 535 (7610). pp. 148-152. ISSN 1476-4687


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 phosphatase. 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 neuroblastoma. SHP2 is ubiquitously expressed and regulates cell survival and proliferation primarily through activation of the RAS-ERK signalling pathway. It is also a key mediator of the programmed cell death 1 (PD-1) and B- and T-lymphocyte attenuator (BTLA) immune checkpoint pathways. Reduction of SHP2 activity suppresses tumour cell growth and is a potential target of cancer therapy. 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.

Item Type: Article
Date Deposited: 13 Jul 2016 23:45
Last Modified: 13 Jul 2016 23:45


Email Alerts

Register with OAK to receive email alerts for saved searches.