PFI-1, a highly selective protein interaction inhibitor, targeting BET Bromodomains
| Autor: | Paul Brennan, Martin Philpott, Dafydd R. Owen, Juerg Schwaller, Panagis Filippakopoulos, Phillippe Taniere, David Da Costa, Tatjana Stankovic, Stefan Knapp, Brendan O'Sullivan, Sarah Picaud, Paul V. Fish, Angeliki Thanasopoulou, Susanne Müller, Mark E. Bunnage, James E. Bradner, Oleg Fedorov |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
Models
Molecular Cancer Research BRD4 Aurora B kinase Down-Regulation Apoptosis Cell Cycle Proteins Cell Growth Processes Article 03 medical and health sciences Mice Structure-Activity Relationship 0302 clinical medicine Downregulation and upregulation Mice Inbred NOD Precursor B-Cell Lymphoblastic Leukemia-Lymphoma Protein Interaction Mapping Animals Humans Molecular Targeted Therapy Phosphorylation Child Transcription factor 030304 developmental biology Transcriptionally active chromatin 0303 health sciences biology Nuclear Proteins Molecular biology Xenograft Model Antitumor Assays 3. Good health Bromodomain Cell biology Protein Structure Tertiary Histone Oncology Acetylation 030220 oncology & carcinogenesis biology.protein Quinazolines Transcription Factors |
| Zdroj: | CANCER RESEARCH |
| Popis: | 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. Cancer Res; 73(11); 3336–46. ©2013 AACR. |
| Databáze: | OpenAIRE |
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