Abstract
PTP1B, a validated therapeutic target for diabetes and obesity, has a critical positive role in HER2 signaling in breast tumorigenesis. Efforts to develop therapeutic inhibitors of PTP1B have been frustrated by the chemical properties of the active site. We define a new mechanism of allosteric inhibition that targets the C-terminal, noncatalytic segment of PTP1B. We present what is to our knowledge the first ensemble structure of PTP1B containing this intrinsically disordered segment, within which we identified a binding site for the small-molecule inhibitor MSI-1436. We demonstrate binding to a second site close to the catalytic domain, with cooperative effects between the two sites locking PTP1B in an inactive state. MSI-1436 antagonized HER2 signaling, inhibited tumorigenesis in xenografts and abrogated metastasis in the NDL2 mouse model of breast cancer, validating inhibition of PTP1B as a therapeutic strategy in breast cancer. This new approach to inhibition of PTP1B emphasizes the potential of disordered segments of proteins as specific binding sites for therapeutic small molecules.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Allosteric Regulation / drug effects
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Allosteric Site / drug effects*
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Animals
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology*
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Breast Neoplasms / drug therapy
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Breast Neoplasms / enzymology
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Breast Neoplasms / genetics
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Breast Neoplasms / pathology
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Catalytic Domain
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Cholestanes / chemistry
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Cholestanes / pharmacology*
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Female
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Gene Expression Regulation, Neoplastic*
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Humans
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Kinetics
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Mammary Neoplasms, Experimental / drug therapy*
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Mammary Neoplasms, Experimental / enzymology
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Mammary Neoplasms, Experimental / genetics
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Mammary Neoplasms, Experimental / pathology
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Mice
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Models, Molecular
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Molecular Targeted Therapy
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Protein Binding / drug effects
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Protein Structure, Secondary
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Protein Structure, Tertiary
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Protein Tyrosine Phosphatase, Non-Receptor Type 1 / antagonists & inhibitors*
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Protein Tyrosine Phosphatase, Non-Receptor Type 1 / genetics
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Protein Tyrosine Phosphatase, Non-Receptor Type 1 / metabolism
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Receptor, ErbB-2 / genetics
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Receptor, ErbB-2 / metabolism
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Signal Transduction
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Spermine / analogs & derivatives*
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Spermine / chemistry
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Spermine / pharmacology
Substances
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3-N-1(spermine)-7, 24-dihydroxy-5-cholestane 24-sulfate
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Antineoplastic Agents
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Cholestanes
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Spermine
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ERBB2 protein, human
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Receptor, ErbB-2
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PTPN1 protein, human
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Protein Tyrosine Phosphatase, Non-Receptor Type 1