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Dual Allosteric Inhibition of SHP2 Phosphatase

Fodor, Michelle, Price, Edmund, Wang, Ping, Lu, Henry, Argintaru, Andreea, Chen, Zhuoliang, Glick, Meir, Hao, Huaixiang, Kato, Mitsunori, Koenig, Robert, Jonathan, LaRochelle, Liu, Gang, Mcneill, Eric, Majumdar, Dyuti, Nishiguchi, Gisele, Perez, Lawrence, Paris, Greg, Quinn, Christopher, Ramsey, Timothy, Sendzik, Martin, Shultz, Michael, Williams, Sarah, Stams, Travis, Stephen, Blacklow, Acker, Michael and Lamarche, Matthew (2018) Dual Allosteric Inhibition of SHP2 Phosphatase. ACS Chemical Biology.


SHP2 is a cytoplasmic protein tyrosine phosphatase encoded by the PTPN11 gene involved in proliferation, differentiation, and survival. Recently we reported an allosteric mechanism of inhibition that stabilizes the auto-inhibited conformation of SHP2. SHP099 (1) was identified and characterized as a moderately potent, orally bioavailable, allosteric small molecule inhibitor. SHP099 binds to a tunnel-like pocket formed by the confluence of three domains of SHP2. In this report, we describe further screening strategies and tactics that enabled the identification of a second, distinct small molecule allosteric site of SHP2 inhibition. SHP244 (2) was identified and characterized as a weak inhibitor of SHP2 with modest thermal stabilization of the enzyme. X-ray crystallography revealed that like 1, 2 binds and stabilizes the inactive, closed conformation of SHP2 but at a distinct, unexplored binding site- a cleft formed at the interface of the N-terminal SH2 and PTP domains. Derivatization of 2 via structure-based design resulted in an increase in SHP2 thermal stabilization, biochemical inhibition, and subsequent MAPK pathway modulation. Downregulation of DUSP6 mRNA, a downstream MAPK pathway marker, was observed in KYSE-520 cancer cells. Remarkably, simultaneous occupation of both allosteric sites by 1 and 2 was possible, as characterized by cooperative biochemical inhibition experiments and X-ray crystallography. Combining an allosteric site 1 inhibitor with an allosteric site 2 inhibitor led to enhanced pharmacological pathway inhibition in cells. This work illustrates a rare example of dual targeted protein inhibition, demonstrates screening methodology and tactics to identify allosteric inhibitors, and enables further interrogation of SHP2 in cancer and related pathologies.

Item Type: Article
Date Deposited: 20 Jan 2018 00:45
Last Modified: 20 Jan 2018 00:45


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