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