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Small-molecule antagonists of Myc/Max dimerization inhibit Myc-induced transformation of chicken embryo fibroblasts

Academic Article
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Overview

related to degree

  • Goldberg, Joel, Ph.D. in Chemistry, Scripps Research 1994 - 2000

authors

  • Berg, T.
  • Cohen, S. B.
  • Desharnais, J.
  • Sonderegger, C.
  • Maslyar, D. J.
  • Goldberg, Joel
  • Boger, Dale
  • Vogt, Peter K.

publication date

  • March 2002

journal

  • Proceedings of the National Academy of Sciences of the United States of America  Journal

abstract

  • Myc is a transcriptional regulator of the basic helix-loop-helix leucine zipper protein family. It has strong oncogenic potential, mutated or virally transduced forms of Myc induce lymphoid tumors in animals, and deregulated expression of Myc is associated with numerous types of human cancers. For its oncogenic activity, Myc must dimerize with the ubiquitously expressed basic helix-loop-helix leucine zipper protein Max. This requirement for dimerization may allow control of Myc activity with small molecules that interfere with Myc/Max dimerization. We have measured Myc/Max dimerization with fluorescence resonance energy transfer and have screened combinatorial chemical libraries for inhibitors of dimerization. Candidate inhibitors were isolated from a peptidomimetics library. Inhibition of Myc/Max interaction was validated by ELISA and electrophoretic mobility-shift assay. Two of the candidate inhibitors also interfere with Myc-induced oncogenic transformation in chicken embryo fibroblast cultures. Our work provides proof of principle for the identification of small molecule inhibitors of protein-protein interactions by using high-throughput screens of combinatorial chemical libraries.

subject areas

  • Animals
  • Base Sequence
  • Basic-Leucine Zipper Transcription Factors
  • Cell Transformation, Neoplastic
  • Chick Embryo
  • DNA
  • DNA-Binding Proteins
  • Dimerization
  • Dose-Response Relationship, Drug
  • Electrophoretic Mobility Shift Assay
  • Energy Transfer
  • Enzyme-Linked Immunosorbent Assay
  • Fibroblasts
  • Fluorescence
  • Inhibitory Concentration 50
  • Pharmaceutical Preparations
  • Protein Binding
  • Proto-Oncogene Proteins c-myc
  • Transcription Factors
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Identity

PubMed Central ID

  • PMC122609

International Standard Serial Number (ISSN)

  • 0027-8424

Digital Object Identifier (DOI)

  • 10.1073/pnas.062036999

PubMed ID

  • 11891322
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Additional Document Info

start page

  • 3830

end page

  • 3835

volume

  • 99

issue

  • 6

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