2. Academic Validation
  3. Inhibitor of MYC identified in a Kröhnke pyridine library

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.
Jonathan R Hart 1,  Amanda L Garner 2,  Jing Yu 2,  Yoshihiro Ito 1,  Minghao Sun 1,  Lynn Ueno 1,  Jin-Kyu Rhee 2,  Michael M Baksh 2,  Eduard Stefan 3,  Markus Hartl 3,  Klaus Bister 3,  Peter K Vogt 4,  Kim D Janda 5
Affiliations

Affiliations

  • 1 Departments of Molecular and Experimental Medicine and.
  • 2 Chemistry, The Scripps Research Institute, La Jolla, CA 92037; and.
  • 3 Institute of Biochemistry, University of Innsbruck, 6020 Innsbruck, Austria.
  • 4 Departments of Molecular and Experimental Medicine and pkvogt@scripps.edu kdjanda@scripps.edu.
  • 5 Chemistry, The Scripps Research Institute, La Jolla, CA 92037; and pkvogt@scripps.edu kdjanda@scripps.edu.
PMID: 25114221 DOI: 10.1073/pnas.1319488111
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.

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