2. Academic Validation
  3. Dual-activity PI3K-BRD4 inhibitor for the orthogonal inhibition of MYC to block tumor growth and metastasis

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

  • Proc Natl Acad Sci U S A. 2017 Feb 14;114(7):E1072-E1080. doi: 10.1073/pnas.1613091114.
Forest H Andrews 1,  Alok R Singh 2 3,  Shweta Joshi 2 3,  Cassandra A Smith 4,  Guillermo A Morales 5,  Joseph R Garlich 5,  Donald L Durden 6 3 5,  Tatiana G Kutateladze 7 4
Affiliations

Affiliations

  • 1 Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045.
  • 2 Division of Pediatric Hematology-Oncology, Department of Pediatrics, Moores Cancer Center, UC San Diego School of Medicine, La Jolla, CA 92130.
  • 3 Rady Children's Hospital San Diego, San Diego, CA 92123.
  • 4 Program in Structural Biology and Biochemistry, University of Colorado School of Medicine, Aurora, CO 80045.
  • 5 SignalRx Pharmaceuticals, Inc., San Diego, CA 92130.
  • 6 Division of Pediatric Hematology-Oncology, Department of Pediatrics, Moores Cancer Center, UC San Diego School of Medicine, La Jolla, CA 92130; [email protected] [email protected].
  • 7 Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045; [email protected] [email protected].
PMID: 28137841 DOI: 10.1073/pnas.1613091114
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 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, 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.

Keywords

BRD4; MYC; PI3K; bromodomain; inhibitor.

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