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PFI-1, a highly selective protein interaction inhibitor, targeting BET Bromodomains

Picaud, Sarah and Da Costa, David and Thanasopoulou, Angeliki and Filippakopoulos, Panagis and Fish, Paul V. and Philpott, Martin and Fedorov, Oleg and Brennan, Paul and Bunnage, Mark E. and Owen, Dafydd R. and Bradner, James E. and Taniere, Philippe and O'Sullivan, Brendan and Müller, Susanne and Schwaller, Juerg and Stankovic, Tatjana and Knapp, Stefan. (2013) PFI-1, a highly selective protein interaction inhibitor, targeting BET Bromodomains. Cancer Research, 73 (11). pp. 3336-3346.

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Official URL: https://edoc.unibas.ch/62072/

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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.
Faculties and Departments:03 Faculty of Medicine > Bereich Kinder- und Jugendheilkunde (Klinik) > Kinder- und Jugendheilkunde (UKBB) > Kindliche Leukämie (Schwaller)
03 Faculty of Medicine > Departement Klinische Forschung > Bereich Kinder- und Jugendheilkunde (Klinik) > Kinder- und Jugendheilkunde (UKBB) > Kindliche Leukämie (Schwaller)
03 Faculty of Medicine > Departement Biomedizin > Department of Biomedicine, University Children's Hospital > Childhood Leukemia (Schwaller)
UniBasel Contributors:Schwaller, Jürg
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:American Association for Cancer Research
ISSN:0008-5472
e-ISSN:1538-7445
Note:Publication type according to Uni Basel Research Database: Journal article
Identification Number:
Last Modified:28 Jul 2020 11:54
Deposited On:28 Jul 2020 11:54

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