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Covalent Small Molecule Inhibitors of Ca2+-Bound S100B.

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Title: Covalent Small Molecule Inhibitors of Ca2+-Bound S100B.
Authors: Cavalier, Michael C.1, Pierce, Adam D.1, Wilder, Paul T.1,2, Alasady, Milad J.1, Hartman, Kira G.1, Neau, David B.3, Foley, Timothy L.4, Jadhav, Ajit4, Maloney, David J.4, Simeonov, Anton4, Toth, Eric A.1,2, Weber, David J.1,2 dweber@som.umaryland.edu
Source: Biochemistry. 10/28/2014, Vol. 53 Issue 42, p6628-6640. 13p.
Subjects: Small molecules, Pharmacology, Molecules, Organic compounds, Melanoma
Abstract: Elevated levels of the tumor marker S100B are observed in malignant melanoma, and this EF-hand-containing protein was shown to directly bind wild-type (wt) p53 in a Ca2+-dependent manner, dissociate the p53 tetramer, and inhibit its tumor suppression functions. Likewise, inhibiting S100B with small interfering RNA (siRNAS100B) is sufficient to restore wild-type p53 levels and its downstream gene products and induce the arrest of cell growth and UV-dependent apoptosis in malignant melanoma. Therefore, it is a goal to develop S100B inhibitors (SBiXs) that inhibit the S100B-p53 complex and restore active p53 in this deadly cancer. Using a structure-activity relationship by nuclear magnetic resonance approach (SAR by NMR), three persistent binding pockets are found on S100B, termed sites 1-3. While inhibitors that simultaneously bind sites 2 and 3 are in place, no molecules that simultaneously bind all three persistent sites are available. For this purpose, Cys84 was used in this study as a potential means to bridge sites 1 and 2 because it is located in a small crevice between these two deeper pockets on the protein. Using a fluorescence polarization competition assay, several Cys84-modified S100B complexes were identified and examined further. For five such SBiX-S100B complexes, crystallographic structures confirmed their covalent binding to Cys84 near site 2 and thus present straightforward chemical biology strategies for bridging sites 1 and 3. Importantly, one such compound, SC1982, showed an Sl00B-dependent death response in assays with WM115 malignant melanoma cells, so it will be particularly useful for the design of SBiX molecules with improved affinity and specificity. [ABSTRACT FROM AUTHOR]
Copyright of Biochemistry is the property of American Chemical Society and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
Database: Engineering Source
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DbLabel: Engineering Source
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  Data: Covalent Small Molecule Inhibitors of Ca<superscript>2+</superscript>-Bound S100B.
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  Data: <searchLink fieldCode="AR" term="%22Cavalier%2C+Michael+C%2E%22">Cavalier, Michael C.</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Pierce%2C+Adam+D%2E%22">Pierce, Adam D.</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Wilder%2C+Paul+T%2E%22">Wilder, Paul T.</searchLink><relatesTo>1,2</relatesTo><br /><searchLink fieldCode="AR" term="%22Alasady%2C+Milad+J%2E%22">Alasady, Milad J.</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Hartman%2C+Kira+G%2E%22">Hartman, Kira G.</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Neau%2C+David+B%2E%22">Neau, David B.</searchLink><relatesTo>3</relatesTo><br /><searchLink fieldCode="AR" term="%22Foley%2C+Timothy+L%2E%22">Foley, Timothy L.</searchLink><relatesTo>4</relatesTo><br /><searchLink fieldCode="AR" term="%22Jadhav%2C+Ajit%22">Jadhav, Ajit</searchLink><relatesTo>4</relatesTo><br /><searchLink fieldCode="AR" term="%22Maloney%2C+David+J%2E%22">Maloney, David J.</searchLink><relatesTo>4</relatesTo><br /><searchLink fieldCode="AR" term="%22Simeonov%2C+Anton%22">Simeonov, Anton</searchLink><relatesTo>4</relatesTo><br /><searchLink fieldCode="AR" term="%22Toth%2C+Eric+A%2E%22">Toth, Eric A.</searchLink><relatesTo>1,2</relatesTo><br /><searchLink fieldCode="AR" term="%22Weber%2C+David+J%2E%22">Weber, David J.</searchLink><relatesTo>1,2</relatesTo><i> dweber@som.umaryland.edu</i>
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  Data: <searchLink fieldCode="JN" term="%22Biochemistry%22">Biochemistry</searchLink>. 10/28/2014, Vol. 53 Issue 42, p6628-6640. 13p.
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  Data: <searchLink fieldCode="DE" term="%22Small+molecules%22">Small molecules</searchLink><br /><searchLink fieldCode="DE" term="%22Pharmacology%22">Pharmacology</searchLink><br /><searchLink fieldCode="DE" term="%22Molecules%22">Molecules</searchLink><br /><searchLink fieldCode="DE" term="%22Organic+compounds%22">Organic compounds</searchLink><br /><searchLink fieldCode="DE" term="%22Melanoma%22">Melanoma</searchLink>
– Name: Abstract
  Label: Abstract
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  Data: Elevated levels of the tumor marker S100B are observed in malignant melanoma, and this EF-hand-containing protein was shown to directly bind wild-type (wt) p53 in a Ca2+-dependent manner, dissociate the p53 tetramer, and inhibit its tumor suppression functions. Likewise, inhibiting S100B with small interfering RNA (siRNAS100B) is sufficient to restore wild-type p53 levels and its downstream gene products and induce the arrest of cell growth and UV-dependent apoptosis in malignant melanoma. Therefore, it is a goal to develop S100B inhibitors (SBiXs) that inhibit the S100B-p53 complex and restore active p53 in this deadly cancer. Using a structure-activity relationship by nuclear magnetic resonance approach (SAR by NMR), three persistent binding pockets are found on S100B, termed sites 1-3. While inhibitors that simultaneously bind sites 2 and 3 are in place, no molecules that simultaneously bind all three persistent sites are available. For this purpose, Cys84 was used in this study as a potential means to bridge sites 1 and 2 because it is located in a small crevice between these two deeper pockets on the protein. Using a fluorescence polarization competition assay, several Cys84-modified S100B complexes were identified and examined further. For five such SBiX-S100B complexes, crystallographic structures confirmed their covalent binding to Cys84 near site 2 and thus present straightforward chemical biology strategies for bridging sites 1 and 3. Importantly, one such compound, SC1982, showed an Sl00B-dependent death response in assays with WM115 malignant melanoma cells, so it will be particularly useful for the design of SBiX molecules with improved affinity and specificity. [ABSTRACT FROM AUTHOR]
– Name: AbstractSuppliedCopyright
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  Data: <i>Copyright of Biochemistry is the property of American Chemical Society and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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        Value: 10.1021/bi5005552
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        Text: English
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