Inhibitor of MYC identified in a Krohnke pyridine library.

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Hart JR, Garner AL, Yu J, Ito Y, Sun M, Ueno L, Rhee JK, Baksh MM, Stefan E, Hartl M, Bister K, Vogt PK, Janda KD

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

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 Krohnke 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.

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