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PFI-1, a highly selective protein interaction inhibitor, targeting BET Bromodomains.
- Source :
-
Cancer research [Cancer Res] 2013 Jun 01; Vol. 73 (11), pp. 3336-46. Date of Electronic Publication: 2013 Apr 10. - Publication Year :
- 2013
-
Abstract
- 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.<br /> (©2013 AACR.)
- Subjects :
- Animals
Apoptosis physiology
Cell Cycle Proteins
Cell Growth Processes physiology
Child
Down-Regulation
Humans
Mice
Mice, Inbred NOD
Models, Molecular
Molecular Targeted Therapy
Nuclear Proteins chemistry
Nuclear Proteins metabolism
Phosphorylation
Precursor B-Cell Lymphoblastic Leukemia-Lymphoma metabolism
Protein Interaction Mapping
Protein Structure, Tertiary
Structure-Activity Relationship
Transcription Factors chemistry
Transcription Factors metabolism
Xenograft Model Antitumor Assays
Nuclear Proteins antagonists & inhibitors
Precursor B-Cell Lymphoblastic Leukemia-Lymphoma drug therapy
Quinazolines pharmacology
Transcription Factors antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1538-7445
- Volume :
- 73
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Cancer research
- Publication Type :
- Academic Journal
- Accession number :
- 23576556
- Full Text :
- https://doi.org/10.1158/0008-5472.CAN-12-3292