Browsing by Subject "pTyr mimetics"

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    Cefsulodin Inspired Potent and Selective Inhibitors of mPTPB, a Virulent Phosphatase from Mycobacterium tuberculosis
    (ACS Publications, 2015-12-10) He, Rongjun; Yu, Zhi-Hong; Zhang, Ruo-Yu; Wu, Li; Gunawan, Andrea M.; Zhang, Zhong-Yin; Department of Biochemistry & Molecular Biology, IU School of Medicine
    mPTPB is a virulent phosphatase from Mycobacterium tuberculosis and a promising therapeutic target for tuberculosis. To facilitate mPTPB-based drug discovery, we identified α-sulfophenylacetic amide (SPAA) from cefsulodin, a third generation β-lactam cephalosporin antibiotic, as a novel pTyr pharmacophore for mPTPB. Structure-guided and fragment-based optimization of SPAA led to the most potent and selective mPTPB inhibitor 9, with a K i of 7.9 nM and more than 10,000-fold preference for mPTPB over a large panel of 25 phosphatases. Compound 9 also exhibited excellent cellular activity and specificity in blocking mPTPB function in macrophage. Given its novel structure, modest molecular mass, and extremely high ligand efficiency (0.46), compound 9 represents an outstanding lead compound for anti-TB drug discovery targeting mPTPB.
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    Exploring the Existing Drug Space for Novel pTyr Mimetic and SHP2 Inhibitors
    (American Chemical Society, 2015-07-09) He, Rongjun; Yu, Zhi-Hong; Zhang, Ruo-Yu; Wu, Li; Gunawan, Andrea M.; Lane, Brandon S.; Shim, Joong S.; Zeng, Li-Fan; He, Yantao; Chen, Lan; Wells, Clark D.; Liu, Jun O.; Zhang, Zhong-Yin; Department of Biochemistry & Molecular Biology, IU School of Medicine
    Protein 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.