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PMID: 11891322 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

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

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 99 ·No. 6 ·2002-03-19 ·Pages 3830-5

Berg T, Cohen SB, Desharnais J, Sonderegger C, Maslyar DJ, Goldberg J, Boger DL, Vogt PK

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.

MeSH Terms
Animals Base Sequence Basic-Leucine Zipper Transcription Factors Cell Transformation, Neoplastic/drug effects Chick Embryo DNA/genetics,metabolism DNA-Binding Proteins/antagonists & inhibitors,metabolism Dimerization Dose-Response Relationship, Drug Electrophoretic Mobility Shift Assay Energy Transfer Enzyme-Linked Immunosorbent Assay Fibroblasts/drug effects,metabolism,pathology Fluorescence Inhibitory Concentration 50 Pharmaceutical Preparations/chemistry Protein Binding/drug effects Proto-Oncogene Proteins c-myc/antagonists & inhibitors,metabolism Transcription Factors
Chemicals
Basic-Leucine Zipper Transcription Factors DNA-Binding Proteins Myc associated factor X Pharmaceutical Preparations Proto-Oncogene Proteins c-myc Transcription Factors DNA
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Berg Thorsten
Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Cohen Steven B
Desharnais Joel
Sonderegger Corinna
Maslyar Daniel J
Goldberg Joel
Boger Dale L
Vogt Peter K
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.062036999
Published
2002-03-19
Epub
2002-00-12
Pages
3830-5
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC122609
Subset
IM
Grants
NCI NIH HHS · P01 CA078045 · United States
NIDDK NIH HHS · T32 DK007022 · United States
NIDDK NIH HHS · 5 T32 DK07022 · United States
NCI NIH HHS · P0I CA 78045 · United States
External Links
PubMed source DOI: 10.1073/pnas.062036999 PMC Full Text View journal details
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