Dual-activity PI3K-BRD4 inhibitor for the orthogonal inhibition of MYC to block tumor growth and metastasis

Forest H. Andrews, Alok R. Singh, Shweta Joshi, Cassandra A. Smith, Guillermo A. Morales, Joseph R. Garlich, Donald L. Durden, Tatiana G. Kutateladze

Research output: Contribution to journalArticle

47 Scopus citations

Abstract

MYC is a major cancer driver but is documented to be a difficult therapeutic target itself. Here, we report on the biological activity, the structural basis, and therapeutic effects of the family of multi-targeted compounds that simultaneously disrupt functions of two critical MYC-mediating factors through inhibiting the acetyllysine binding of BRD4 and the kinase activity of PI3K. We show that the dual-action inhibitor impairs PI3K/BRD4 signaling in vitro and in vivo and affords maximal MYC down-regulation. The concomitant inhibition of PI3K and BRD4 blocks MYC expression and activation, promotes MYC degradation, and markedly inhibits cancer cell growth and metastasis. Collectively, our findings suggest that the dual-activity inhibitor represents a highly promising lead compound for the development of novel anticancer therapeutics.

Original languageEnglish (US)
Pages (from-to)E1072-E1080
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number7
DOIs
StatePublished - Feb 14 2017

Keywords

  • BRD4
  • Bromodomain
  • Inhibitor
  • MYC
  • PI3K

ASJC Scopus subject areas

  • General

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    Andrews, F. H., Singh, A. R., Joshi, S., Smith, C. A., Morales, G. A., Garlich, J. R., Durden, D. L., & Kutateladze, T. G. (2017). Dual-activity PI3K-BRD4 inhibitor for the orthogonal inhibition of MYC to block tumor growth and metastasis. Proceedings of the National Academy of Sciences of the United States of America, 114(7), E1072-E1080. https://doi.org/10.1073/pnas.1613091114