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 journalArticlepeer-review

49 Scopus citations


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
Issue number7
StatePublished - Feb 14 2017


  • BRD4
  • Bromodomain
  • Inhibitor
  • MYC
  • PI3K

ASJC Scopus subject areas

  • General

Fingerprint Dive into the research topics of 'Dual-activity PI3K-BRD4 inhibitor for the orthogonal inhibition of MYC to block tumor growth and metastasis'. Together they form a unique fingerprint.

Cite this