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PFI-1, a Highly Selective Protein Interaction Inhibitor, Targeting BET Bromodomains

PFI-1, a Highly Selective Protein Interaction Inhibitor, Targeting BET Bromodomains

Sarah Picaud, David Da Costa, Angeliki Thanasopoulou, Panagis Filippakopoulos, Paul V Fish, Martin Philpott, Oleg Fedorov, Paul Brennan, Mark E Bunnage, Dafydd R Owen, James E Bradner, Philippe Taniere, etc.

Cancer Res. 2013 Jun 1;73(11):3336-46.

PMID: 23576556

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP1403764726	PFI-1		1403764-72-6	Price

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