kj-pyr-9 and Cell-Transformation--Neoplastic

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.

Topics: Animals; Antineoplastic Agents; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Cell Proliferation; Cell Transformation, Neoplastic; Cells, Cultured; Chick Embryo; Drug Evaluation, Preclinical; Female; Fluorescence Polarization; Genes, myc; Humans; Interferometry; Mice; Mice, Nude; Multiprotein Complexes; Protein Interaction Domains and Motifs; Proto-Oncogene Proteins c-myc; Pyridines; Pyrimidines; Xenograft Model Antitumor Assays