Related Experiment Video
Updated: May 12, 2026
Chemical Inactivation of the E3 Ubiquitin Ligase Cereblon by Pomalidomide-based Homo-PROTACs
Published on: May 15, 2019
PFI-1, a highly selective protein interaction inhibitor, targeting BET Bromodomains
Sarah Picaud1, David Da Costa, Angeliki Thanasopoulou
1Structural Genomics Consortium and Target Discovery Institute, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, USA.
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.
Insights
A new drug, PFI-1, targets Bromo and extra terminal (BET) proteins, inhibiting cancer cell growth. PFI-1 blocks key interactions, downregulates MYC, and induces apoptosis, offering a novel cancer treatment strategy.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Bromo and extra terminal (BET) proteins regulate gene expression crucial for cell growth and survival.
- BET proteins bind to acetylated histones via their bromodomains (BRD), a key interaction in transcription.
- Inhibiting BET-histone interactions offers a potential strategy for cancer therapy by downregulating oncogenes.
Purpose of the Study:
- To present PFI-1, a novel inhibitor targeting the interaction between BET bromodomains (BRD) and acetylated histone tails.
- To investigate the molecular mechanism and antiproliferative effects of PFI-1 in cancer cells.
Main Methods:
- Cocrystallography to determine the binding mode of PFI-1 to BRD2 and BRD4.
- Cell-based assays to assess antiproliferative effects, cell-cycle progression, gene expression changes (MYC), apoptosis induction, and differentiation.
- Analysis of downstream signaling pathways, including Aurora B kinase and H3S10 phosphorylation.
Main Results:
- PFI-1 acts as an acetyl-lysine (Kac) mimetic, effectively binding to the Kac site in BRD4 and BRD2.
- PFI-1 demonstrated potent antiproliferative and anti-clonogenic effects on leukemic cell lines.
- Treatment with PFI-1 induced G1 cell-cycle arrest, MYC downregulation, apoptosis, and differentiation in leukemic cells.
- PFI-1 significantly downregulated Aurora B kinase, impacting H3S10 phosphorylation.
Conclusions:
- PFI-1 is a potent and selective inhibitor of BET bromodomains (BRD).
- PFI-1 exhibits significant anticancer activity by disrupting key oncogenic pathways.
- PFI-1 represents a promising therapeutic agent for cancers driven by BET protein activity, including leukemia.
More Related Videos
08:07Identification of Inositol Phosphate or Phosphoinositide Interacting Proteins by Affinity Chromatography Coupled to Western Blot or Mass Spectrometry
Published on: July 26, 2019
12:42Photoactivated Localization Microscopy with Bimolecular Fluorescence Complementation (BiFC-PALM)
Published on: December 22, 2015
Related Concept Videos
02:04Protein-protein Interfaces
01:42Phosphoinositides and PIPs
Different phosphoinositides are synthesized and recruited on the cytosolic face of the plasma membrane. The localization of specific phosphoinositides concentrated in separate membrane...