title: PFI-1, a highly selective protein interaction inhibitor, targeting BET Bromodomains.
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.
authors.affiliation: Structural Genomics Consortium and Target Discovery Institute, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Picaud
authors.forename: David
authors.initials: D
authors.lastname: Da Costa
authors.forename: Angeliki
authors.initials: A
authors.lastname: Thanasopoulou
authors.forename: Panagis
authors.initials: P
authors.lastname: Filippakopoulos
authors.forename: Paul V
authors.initials: PV
authors.lastname: Fish
authors.forename: Martin
authors.initials: M
authors.lastname: Philpott
authors.forename: Oleg
authors.initials: O
authors.lastname: Fedorov
authors.forename: Paul
authors.initials: P
authors.lastname: Brennan
authors.forename: Mark E
authors.initials: ME
authors.lastname: Bunnage
authors.forename: Dafydd R
authors.initials: DR
authors.lastname: Owen
authors.forename: James E
authors.initials: JE
authors.lastname: Bradner
authors.forename: Philippe
authors.initials: P
authors.lastname: Taniere
authors.forename: Brendan
authors.initials: B
authors.lastname: O'Sullivan
authors.forename: Susanne
authors.initials: S
authors.lastname: Müller
authors.forename: Juerg
authors.initials: J
authors.lastname: Schwaller
authors.forename: Tatjana
authors.initials: T
authors.lastname: Stankovic
authors.forename: Stefan
authors.initials: S
authors.lastname: Knapp
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D018797:Cell Cycle Proteins; D048708:Cell Growth Processes / Q000502:physiology; D002648:Child; D015536:Down-Regulation; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D008958:Models, Molecular; D058990:Molecular Targeted Therapy; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D010766:Phosphorylation; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000378:metabolism; D025941:Protein Interaction Mapping; D017434:Protein Structure, Tertiary; D011799:Quinazolines / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D000092468:Bromodomain Containing Proteins
chemical_list: D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D011799:Quinazolines; D014157:Transcription Factors; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins