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Inhibitor of MYC identified in a Krohnke pyridine library.

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.

SUBMITTER: Hart JR

PROVIDER: S-EPMC4151726 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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Inhibitor of MYC identified in a Kröhnke pyridine library.

Hart Jonathan R JR Garner Amanda L AL Yu Jing J Ito Yoshihiro Y Sun Minghao M Ueno Lynn L Rhee Jin-Kyu JK Baksh Michael M MM Stefan Eduard E Hartl Markus M Bister Klaus K Vogt Peter K PK Janda Kim D KD

Proceedings of the National Academy of Sciences of the United States of America 20140811 34

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 wea ...[more]

PMID: 25114221

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