Browsing by Subject "Protein tyrosine phosphatase"

Now showing 1 - 3 of 3
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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.
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    SHP2 phosphatase as a novel therapeutic target for melanoma treatment
    (Impact Journals, 2016-11-08) Zhang, Ruo-Yu; Yu, Zhi-Hong; Zeng, Lifan; Zhang, Sheng; Bai, Yunpeng; Miao, Jinmin; Chen, Lan; Xie, Jingwu; Zhang, Zhong-Yin; Department of Biochemistry & Molecular Biology, IU School of Medicine
    Melanoma ranks among the most aggressive and deadly human cancers. Although a number of targeted therapies are available, they are effective only in a subset of patients and the emergence of drug resistance often reduces durable responses. Thus there is an urgent need to identify new therapeutic targets and develop more potent pharmacological agents for melanoma treatment. Herein we report that SHP2 levels are frequently elevated in melanoma, and high SHP2 expression is significantly associated with more metastatic phenotype and poorer prognosis. We show that SHP2 promotes melanoma cell viability, motility, and anchorage-independent growth, through activation of both ERK1/2 and AKT signaling pathways. We demonstrate that SHP2 inhibitor 11a-1 effectively blocks SHP2-mediated ERK1/2 and AKT activation and attenuates melanoma cell viability, migration and colony formation. Most importantly, SHP2 inhibitor 11a-1 suppresses xenografted melanoma tumor growth, as a result of reduced tumor cell proliferation and enhanced tumor cell apoptosis. Taken together, our data reveal SHP2 as a novel target for melanoma and suggest SHP2 inhibitors as potential novel therapeutic agents for melanoma treatment.