Format

Send to

Choose Destination
Nat Chem Biol. 2016 Dec;12(12):1089-1096. doi: 10.1038/nchembio.2209. Epub 2016 Oct 24.

Design and characterization of bivalent BET inhibitors.

Author information

1
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
2
Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
3
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

Abstract

Cellular signaling is often propagated by multivalent interactions. Multivalency creates avidity, allowing stable biophysical recognition. Multivalency is an attractive strategy for achieving potent binding to protein targets, as the affinity of bivalent ligands is often greater than the sum of monovalent affinities. The bromodomain and extraterminal domain (BET) family of transcriptional coactivators features tandem bromodomains through which BET proteins bind acetylated histones and transcription factors. All reported antagonists of the BET protein BRD4 bind in a monovalent fashion. Here we describe, to our knowledge for the first time, a bivalent BET bromodomain inhibitor-MT1-which has unprecedented potency. Biophysical and biochemical studies suggest MT1 is an intramolecular bivalent BRD4 binder that is more than 100-fold more potent, in cellular assays, than the corresponding monovalent antagonist, JQ1. MT1 significantly (P < 0.05) delayed leukemia progression in mice, as compared to JQ1. These data qualify a powerful chemical probe for BET bromodomains and a rationale for further development of multidomain inhibitors of epigenetic reader proteins.

PMID:
27775715
PMCID:
PMC5117811
DOI:
10.1038/nchembio.2209
[Indexed for MEDLINE]
Free PMC Article

MeSH terms, Substances, Secondary source ID, Grant support

MeSH terms

Substances

Secondary source ID

Grant support

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center