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Research Article

Inhibitor of MYC identified in a Kröhnke pyridine library

Jonathan R. Hart, Amanda L. Garner, Jing Yu, Yoshihiro Ito, Minghao Sun, Lynn Ueno, Jin-Kyu Rhee, Michael M. Baksh, Eduard Stefan, Markus Hartl, Klaus Bister, Peter K. Vogt, and Kim D. Janda
PNAS first published August 11, 2014; https://doi.org/10.1073/pnas.1319488111
Jonathan R. Hart
Departments of aMolecular and Experimental Medicine and
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Amanda L. Garner
bChemistry, The Scripps Research Institute, La Jolla, CA 92037; and
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Jing Yu
bChemistry, The Scripps Research Institute, La Jolla, CA 92037; and
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Yoshihiro Ito
Departments of aMolecular and Experimental Medicine and
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Minghao Sun
Departments of aMolecular and Experimental Medicine and
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Lynn Ueno
Departments of aMolecular and Experimental Medicine and
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Jin-Kyu Rhee
bChemistry, The Scripps Research Institute, La Jolla, CA 92037; and
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Michael M. Baksh
bChemistry, The Scripps Research Institute, La Jolla, CA 92037; and
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Eduard Stefan
cInstitute of Biochemistry, University of Innsbruck, 6020 Innsbruck, Austria
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Markus Hartl
cInstitute of Biochemistry, University of Innsbruck, 6020 Innsbruck, Austria
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Klaus Bister
cInstitute of Biochemistry, University of Innsbruck, 6020 Innsbruck, Austria
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Peter K. Vogt
Departments of aMolecular and Experimental Medicine and
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  • For correspondence: pkvogt@scripps.edu kdjanda@scripps.edu
Kim D. Janda
bChemistry, The Scripps Research Institute, La Jolla, CA 92037; and
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  • For correspondence: pkvogt@scripps.edu kdjanda@scripps.edu
  1. Edited by Dennis A. Carson, University of California, San Diego, La Jolla, CA, and approved July 18, 2014 (received for review October 17, 2013)

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Significance

MYC is an essential transcriptional regulator that controls cell proliferation. Elevated MYC is a driving force in most human cancers, yet MYC has been an exceedingly challenging target for small-molecule inhibitors. Here we describe a novel MYC inhibitor that interacts directly with MYC and interferes with its transcriptional and oncogenic activities.

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.

  • transcriptional control
  • protein–protein interactions
  • xenograft
  • combinatorial library
  • gene signature

Footnotes

  • ↵1J.R.H. and A.L.G. contributed equally to this work.

  • ↵2Present address: Western Seoul Center, Korea Basic Science Institute, Seoul 120-140, Republic of Korea.

  • ↵3To whom correspondence may be addressed. Email: pkvogt{at}scripps.edu or kdjanda{at}scripps.edu.
  • Author contributions: J.R.H., A.L.G., K.B., P.K.V., and K.D.J. designed research; J.R.H., A.L.G., J.Y., Y.I., M.S., L.U., J.-K.R., M.M.B., E.S., M.H., K.B., P.K.V., and K.D.J. performed research; J.R.H. and A.L.G. contributed new reagents/analytic tools; J.R.H., A.L.G., K.B., P.K.V., and K.D.J. analyzed data; and J.R.H., A.L.G., K.B., P.K.V., and K.D.J. wrote the paper.

  • The authors declare no conflict of interest.

  • This article is a PNAS Direct Submission.

  • Data deposition: The data reported in this paper have been deposited in the Gene Expression Omnibus (GEO) database, www.ncbi.nlm.nih.gov/geo (accession no. GSE58168).

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1319488111/-/DCSupplemental.

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Small-molecule inhibitor of MYC
Jonathan R. Hart, Amanda L. Garner, Jing Yu, Yoshihiro Ito, Minghao Sun, Lynn Ueno, Jin-Kyu Rhee, Michael M. Baksh, Eduard Stefan, Markus Hartl, Klaus Bister, Peter K. Vogt, Kim D. Janda
Proceedings of the National Academy of Sciences Aug 2014, 201319488; DOI: 10.1073/pnas.1319488111

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Small-molecule inhibitor of MYC
Jonathan R. Hart, Amanda L. Garner, Jing Yu, Yoshihiro Ito, Minghao Sun, Lynn Ueno, Jin-Kyu Rhee, Michael M. Baksh, Eduard Stefan, Markus Hartl, Klaus Bister, Peter K. Vogt, Kim D. Janda
Proceedings of the National Academy of Sciences Aug 2014, 201319488; DOI: 10.1073/pnas.1319488111
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