期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 114, 期 7, 页码 E1072-E1080出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1613091114
关键词
MYC; bromodomain; BRD4; PI3K; inhibitor
资金
- NIH [R01 GM101664, GM106416, GM100907, R01 CA94233, STTR CA192646, R01 FD04385]
- AHA postdoctoral fellowship
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 multitargeted 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, andmarkedly inhibits cancer cell growth and metastasis. Collectively, our findings suggest that the dualactivity inhibitor represents a highly promising lead compound for the development of novel anticancer therapeutics.
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