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In vitro screening and structural characterization of inhibitors of the S100B-p53 interaction.

Wilder PT, Charpentier TH, Liriano MA, Gianni K, Varney KM, Pozharski E, Coop A, Toth EA, Mackerell AD, Weber DJ
Int J High Throughput Screen 2010 109-126 (2010)
Related entries: 3lk1, 3lle

Cited: 21 times
EuropePMC logo PMID: 21132089

Abstract

S100B is highly over-expressed in many cancers, including malignant melanoma. In such cancers, S100B binds wild-type p53 in a calcium-dependent manner, sequestering it, and promoting its degradation, resulting in the loss of p53-dependent tumor suppression activities. Therefore, S100B inhibitors may be able to restore wild-type p53 levels in certain cancers and provide a useful therapeutic strategy. In this regard, an automated and sensitive fluorescence polarization competition assay (FPCA) was developed and optimized to screen rapidly for lead compounds that bind Ca(2+)-loaded S100B and inhibit S100B target complex formation. A screen of 2000 compounds led to the identification of 26 putative S100B low molecular weight inhibitors. The binding of these small molecules to S100B was confirmed by nuclear magnetic resonance spectroscopy, and additional structural information was provided by x-ray crystal structures of several compounds in complexes with S100B. Notably, many of the identified inhibitors function by chemically modifying Cys84 in protein. These results validate the use of high-throughput FPCA to facilitate the identification of compounds that inhibit S100B. These lead compounds will be the subject of future optimization studies with the ultimate goal of developing a drug with therapeutic activity for the treatment of malignant melanoma and/or other cancers with elevated S100B.

Reviews - 3lk0 mentioned but not cited (1)

  1. The evolution of S100B inhibitors for the treatment of malignant melanoma. Hartman KG, McKnight LE, Liriano MA, Weber DJ. Future Med Chem 5 97-109 (2013)

Articles - 3lk0 mentioned but not cited (4)

  1. A Guided Tour of the Structural Biology of Gaucher Disease: Acid-β-Glucosidase and Saposin C. Lieberman RL. Enzyme Res 2011 973231 (2011)
  2. In vitro screening and structural characterization of inhibitors of the S100B-p53 interaction. Wilder PT, Charpentier TH, Liriano MA, Gianni K, Varney KM, Pozharski E, Coop A, Toth EA, Mackerell AD, Weber DJ. Int J High Throughput Screen 2010 109-126 (2010)
  3. Multiple Evolutionary Origins of Ubiquitous Cu2+ and Zn2+ Binding in the S100 Protein Family. Wheeler LC, Donor MT, Prell JS, Harms MJ. PLoS One 11 e0164740 (2016)
  4. Conservation of Specificity in Two Low-Specificity Proteins. Wheeler LC, Anderson JA, Morrison AJ, Wong CE, Harms MJ. Biochemistry 57 684-695 (2018)


Reviews citing this publication (5)

  1. S100 proteins as therapeutic targets. Bresnick AR. Biophys Rev 10 1617-1629 (2018)
  2. Molecular dynamic simulation insights into the normal state and restoration of p53 function. Fu T, Min H, Xu Y, Chen J, Li G. Int J Mol Sci 13 9709-9740 (2012)
  3. Structural basis for the role of mammalian aldehyde oxidases in the metabolism of drugs and xenobiotics. Romão MJ, Coelho C, Santos-Silva T, Foti A, Terao M, Garattini E, Leimkühler S. Curr Opin Chem Biol 37 39-47 (2017)
  4. A Structural Perspective on Calprotectin as a Ligand of Receptors Mediating Inflammation and Potential Drug Target. Garcia V, Perera YR, Chazin WJ. Biomolecules 12 519 (2022)
  5. Macromolecular structures: Quality assessment and biological interpretation. Salunke DM, Nair DT. IUBMB Life 69 563-571 (2017)

Articles citing this publication (11)

  1. Fluorescence polarization assays in high-throughput screening and drug discovery: a review. Hall MD, Yasgar A, Peryea T, Braisted JC, Jadhav A, Simeonov A, Coussens NP. Methods Appl Fluoresc 4 022001 (2016)
  2. Structural insights into xenobiotic and inhibitor binding to human aldehyde oxidase. Coelho C, Foti A, Hartmann T, Santos-Silva T, Leimkühler S, Romão MJ. Nat Chem Biol 11 779-783 (2015)
  3. S100 proteins as diagnostic and prognostic markers in colorectal and hepatocellular carcinoma. Maletzki C, Bodammer P, Breitrück A, Kerkhoff C. Hepat Mon 12 e7240 (2012)
  4. Target binding to S100B reduces dynamic properties and increases Ca(2+)-binding affinity for wild type and EF-hand mutant proteins. Liriano MA, Varney KM, Wright NT, Hoffman CL, Toth EA, Ishima R, Weber DJ. J Mol Biol 423 365-385 (2012)
  5. Small Molecule Inhibitors of Ca(2+)-S100B Reveal Two Protein Conformations. Cavalier MC, Ansari MI, Pierce AD, Wilder PT, McKnight LE, Raman EP, Neau DB, Bezawada P, Alasady MJ, Charpentier TH, Varney KM, Toth EA, MacKerell AD, Coop A, Weber DJ. J Med Chem 59 592-608 (2016)
  6. The Activation of Protein Kinase A by the Calcium-Binding Protein S100A1 Is Independent of Cyclic AMP. Melville Z, Hernández-Ochoa EO, Pratt SJP, Liu Y, Pierce AD, Wilder PT, Adipietro KA, Breysse DH, Varney KM, Schneider MF, Weber DJ. Biochemistry 56 2328-2337 (2017)
  7. Novel protein-inhibitor interactions in site 3 of Ca(2+)-bound S100B as discovered by X-ray crystallography. Cavalier MC, Melville Z, Aligholizadeh E, Raman EP, Yu W, Fang L, Alasady M, Pierce AD, Wilder PT, MacKerell AD, Weber DJ. Acta Crystallogr D Struct Biol 72 753-760 (2016)
  8. Structural Basis for S100B Interaction with its Target Proteins. Prez KD, Fan L. J Mol Genet Med 12 366 (2018)
  9. Targeting S100 Calcium-Binding Proteins with Small Molecule Inhibitors. Wilder PT, Varney KM, Weber DJ. Methods Mol Biol 1929 291-310 (2019)
  10. Letter Response to Comment on Three X-ray Crystal Structure Papers. Salunke DM, Khan T, Gaur V, Tapryal S, Kaur K. J Immunol 196 524-528 (2016)
  11. Bacteriophage PRD1 as a nanoscaffold for drug loading. Duyvesteyn HME, Santos-Pérez I, Peccati F, Martinez-Castillo A, Walter TS, Reguera D, Goñi FM, Jiménez-Osés G, Oksanen HM, Stuart DI, Abrescia NGA. Nanoscale 13 19875-19883 (2021)


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