Inhibitor of MYC identified in a Kröhnke pyridine library

Proc Natl Acad Sci U S A. 2014 Aug 26;111(34):12556-61. doi: 10.1073/pnas.1319488111. Epub 2014 Aug 11.

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.

Keywords: combinatorial library; gene signature; protein–protein interactions; transcriptional control; xenograft.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / antagonists & inhibitors
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / chemistry
  • Cell Proliferation / drug effects
  • Cell Transformation, Neoplastic / drug effects
  • Cell Transformation, Neoplastic / genetics
  • Cells, Cultured
  • Chick Embryo
  • Drug Evaluation, Preclinical
  • Female
  • Fluorescence Polarization
  • Genes, myc
  • Humans
  • Interferometry
  • Mice
  • Mice, Nude
  • Multiprotein Complexes / antagonists & inhibitors
  • Multiprotein Complexes / chemistry
  • Protein Interaction Domains and Motifs / drug effects
  • Proto-Oncogene Proteins c-myc / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-myc / chemistry
  • Pyridines / chemistry
  • Pyridines / pharmacology*
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology*
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • KJ-Pyr-9
  • MAX protein, human
  • MYC protein, human
  • Multiprotein Complexes
  • Proto-Oncogene Proteins c-myc
  • Pyridines
  • Pyrimidines

Associated data

  • GEO/GSE58168