Inhibitor of MYC identified in a Kröhnke pyridine library

Jonathan R. Hart, Amanda L. Garner, Jing Yu, Yoshihiro Ito, Minghao Sun, Lynn Ueno, Jin Kyu Rhee, Michael M. Baksh, Eduard Stefan, Markus Hartl, Klaus Bister, Peter K. Vogt, Kim D. Janda

Research output: Contribution to journalArticlepeer-review

80 Scopus citations

Abstract

In a fluorescence polarization screen for the MYC-MAX interaction, we have identified a novel small-molecule inhibitor of MYC, KJ-Pyr-9, from a Kröhnke pyridine library. The Kd of KJ-Pyr-9 for MYC in vitro is 6.5 ± 1.0 nM, as determined by backscattering interferometry; KJ-Pyr-9 also interferes with MYC-MAX complex formation in the cell, as shown in a protein fragment complementation assay. KJ-Pyr-9 specifically inhibits MYC-induced oncogenic transformation in cell culture; it has no or only weak effects on the oncogenic activity of several unrelated oncoproteins. KJ-Pyr-9 preferentially interferes with the proliferation of MYC-overexpressing human and avian cells and specifically reduces the MYC-driven transcriptional signature. In vivo, KJ-Pyr-9 effectively blocks the growth of a xenotransplant of MYC-amplified human cancer cells.

Original languageEnglish
Pages (from-to)12556-12561
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number34
DOIs
StatePublished - 26 Aug 2014

Keywords

  • Combinatorial library
  • Gene signature
  • Protein-protein interactions
  • Transcriptional control
  • Xenograft

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