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Bromo and extra terminal (BET) proteins (BRD2, BRD3, BRD4, and BRDT) are transcriptional regulators required for efficient expression of several growth promoting and antiapoptotic genes as well as for cell-cycle progression. BET proteins are recruited on transcriptionally active chromatin via their two N-terminal bromodomains (BRD), a protein interaction module that specifically recognizes acetylated lysine residues in histones H3 and H4. Inhibition of the BET-histone interaction results in transcriptional downregulation of a number of oncogenes, providing a novel pharmacologic strategy for the treatment of cancer. Here, we present a potent and highly selective dihydroquinazoline-2-one inhibitor, PFI-1, which efficiently blocks the interaction of BET BRDs with acetylated histone tails. Cocrystal structures showed that PFI-1 acts as an acetyl-lysine (Kac) mimetic inhibitor efficiently occupying the Kac binding site in BRD4 and BRD2. PFI-1 has antiproliferative effects on leukemic cell lines and efficiently abrogates their clonogenic growth. Exposure of sensitive cell lines with PFI-1 results in G1 cell-cycle arrest, downregulation of MYC expression, as well as induction of apoptosis and induces differentiation of primary leukemic blasts. Intriguingly, cells exposed to PFI-1 showed significant downregulation of Aurora B kinase, thus attenuating phosphorylation of the Aurora substrate H3S10, providing an alternative strategy for the specific inhibition of this well-established oncology target.

Original publication

DOI

10.1158/0008-5472.CAN-12-3292

Type

Journal article

Journal

Cancer Res

Publication Date

01/06/2013

Volume

73

Pages

3336 - 3346

Keywords

Animals, Apoptosis, Cell Cycle Proteins, Cell Growth Processes, Child, Down-Regulation, Humans, Mice, Mice, Inbred NOD, Models, Molecular, Molecular Targeted Therapy, Nuclear Proteins, Phosphorylation, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma, Protein Interaction Mapping, Protein Structure, Tertiary, Quinazolines, Structure-Activity Relationship, Transcription Factors, Xenograft Model Antitumor Assays