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Exploring the Existing Drug Space for Novel pTyr Mimetic and SHP2 Inhibitors
He R.1; Yu Z.-H.1; Zhang R.-Y.1; Wu L.1; Gunawan A.M.1; Lane B.S.1; Shim J.S.2; Zeng L.-F.1; He Y.1; Chen L.1; Wells C.D.1; Liu J.O.2; Zhang Z.-Y.1
2015-07-09
Source PublicationACS Medicinal Chemistry Letters
ISSN19485875
Volume6Issue:7Pages:782-786
AbstractProtein tyrosine phosphatases (PTPs) are potential therapeutic targets for many diseases. Unfortunately, despite considerable drug discovery efforts devoted to PTPs, obtaining selective and cell permeable PTP inhibitors remains highly challenging. We describe a strategy to explore the existing drug space for previously unknown PTP inhibitory activities. This led to the discovery of cefsulodin as an inhibitor of SHP2, an oncogenic phosphatase in the PTP family. Crystal structure analysis of SHP2 interaction with cefsulodin identified sulfophenyl acetic amide (SPAA) as a novel phosphotyrosine (pTyr) mimetic. A structure-guided and SPAA fragment-based focused library approach produced several potent and selective SHP2 inhibitors. Notably, these inhibitors blocked SHP2-mediated signaling events and proliferation in several cancer cell lines. Thus, SPAA may serve as a new platform for developing chemical probes for other PTPs.
Keywordanticancer agents fragment-based library Protein tyrosine phosphatase pTyr mimetics SHP2 inhibitors
DOI10.1021/acsmedchemlett.5b00118
URLView the original
Language英語
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Cited Times [WOS]:14   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionUniversity of Macau
Affiliation1.Indiana University School of Medicine Indianapolis
2.Johns Hopkins University
Recommended Citation
GB/T 7714
He R.,Yu Z.-H.,Zhang R.-Y.,et al. Exploring the Existing Drug Space for Novel pTyr Mimetic and SHP2 Inhibitors[J]. ACS Medicinal Chemistry Letters,2015,6(7):782-786.
APA He R..,Yu Z.-H..,Zhang R.-Y..,Wu L..,Gunawan A.M..,...&Zhang Z.-Y..(2015).Exploring the Existing Drug Space for Novel pTyr Mimetic and SHP2 Inhibitors.ACS Medicinal Chemistry Letters,6(7),782-786.
MLA He R.,et al."Exploring the Existing Drug Space for Novel pTyr Mimetic and SHP2 Inhibitors".ACS Medicinal Chemistry Letters 6.7(2015):782-786.
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