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

  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)

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.

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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