Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• Nature (London), 2016-07, Vol.535 (7610), p.148-152

Ort / Verlag

London: Nature Publishing Group UK

Erscheinungsjahr

2016

Quelle

MEDLINE

Beschreibungen/Notizen

• SHP099, a selective inhibitor of signalling meditator SHP2 with drug-like properties, has an allosteric mechanism of action whereby it stabilizes SHP2 in an auto-inhibited conformation, and suppresses RAS–ERK signalling and proliferation in receptor-tyrosine-kinase-driven cancer cell lines and mouse tumour xenograft models. Potential therapeutic for RTK-driven human cancers The tyrosine phosphatase SHP2 is a key mediator of receptor tyrosine kinase (RTK) signalling, as well as being important in immune checkpoint pathways. Reduction of SHP2 activity suppresses tumour cell growth, and SHP2 is a potential, but so far elusive, therapeutic target in cancer. Pascal Fortin and colleagues report the development of a selective SHP2 inhibitor with drug-like properties. The inhibitor, SHP099, has an allosteric mechanism of action whereby it stabilizes SHP2 in an auto-inhibited conformation. It also suppresses RAS–ERK signalling to inhibit RTK-driven proliferation in human cancer cell lines and mouse tumour xenograft models. 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 1 . 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 1 , 2 , 3 , 4 , 5 . SHP2 is ubiquitously expressed and regulates cell survival and proliferation primarily through activation of the RAS–ERK signalling pathway 2 , 3 . It is also a key mediator of the programmed cell death 1 (PD-1) and B- and T-lymphocyte attenuator (BTLA) immune checkpoint pathways 6 , 7 . Reduction of SHP2 activity suppresses tumour cell growth and is a potential target of cancer therapy 8 , 9 . Here we report the discovery of a highly potent (IC 50  = 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.