Selective targeting of the BRG/PB1 bromodomains impairs embryonic and trophoblast stem cell maintenance

Fedorov, Oleg; Castex, Josefina; Tallant, C.; Owen, Dafydd R.; Martin, Sarah; Aldeghi, Matteo; Monteiro, Octovia; Filippakopoulos, P.; Picaud, S.; Trzupek, John D.; Gerstenberger, Brian S.; Bountra, C.; Willmann, Dominica; Wells, Christopher; Philpott, Martin; Rogers, Catherine; Biggin, Philip C.; Brennan, P.E.; Bunnage, Mark E.; Schüle, Roland; Günther, Thomas; Knapp, Stefan; Müller, Susanne

doi:10.1126/sciadv.1500723

Cited by 117 publications

(190 citation statements)

References 55 publications

(83 reference statements)

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“…Similarly, in Family VIII bromodomains most sites were identified as being poorly stable. The trend of high instability at W4 is in agreement with a previous molecular dynamics study of water thermodynamics in PB1(5) versus BRD4 (1), in which it was hypothesized that the instability at this position is caused by an~90°rotation of a backbone carbonyl group adjacent to W4 10 . The water at site W1 has been shown to be displaceable from the pockets of BRPF1B and PHIP(2) 14,15 .…”

Section: General Approachsupporting

confidence: 79%

“…In 2014, Harner et al 9 reported the discovery an aniline-containing tricyclic fragment that was shown to bind deep into ATAD2, displacing all four conserved water molecules. In 2015, Fedorov et al 10 reported the displacement of all four conserved waters by salicylic acid from the binding pockets of a number of Family VIII bromodomains. The fragment led to the development of a nanomolar ligand, selective for the SMARCA and PB1 bromodomains (Family VIII).…”

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confidence: 99%

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Large-scale analysis of water stability in bromodomain binding pockets with grand canonical Monte Carlo

et al. 2018

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Conserved water molecules are of interest in drug design, as displacement of such waters can lead to higher affinity ligands, and in some cases, contribute towards selectivity. Bromodomains, small protein domains involved in the epigenetic regulation of gene transcription, display a network of four conserved water molecules in their binding pockets and have recently been the focus of intense medicinal chemistry efforts. Understanding why certain bromodomains have displaceable water molecules and others do not is extremely challenging, and it remains unclear which water molecules in a given bromodomain can be targeted for displacement. Here we estimate the stability of the conserved water molecules in 35 bromodomains via binding free energy calculations using all-atom grand canonical Monte Carlo simulations. Encouraging quantitative agreement to the available experimental evidence is found. We thus discuss the expected ease of water displacement in different bromodomains and the implications for ligand selectivity.

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Section: General Approachsupporting

confidence: 79%

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confidence: 99%

Large-scale analysis of water stability in bromodomain binding pockets with grand canonical Monte Carlo

et al. 2018

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“…11 The crystal structure and characterization of the salicylic acid fragment hit 1 have been reported elsewhere. 12 With a weak but ligand efficient fragment hit successfully crystallized in PB1(5), further molecular optimization was guided towards exploiting lipophilic interactions for larger ligands derived from the salicylic acid lead 1 . These changes were designed to enhance potency levels closer to those set as an expectation of a quality chemical probe – around 100nM in a biochemical or biophysical assay.…”

Section: Resultsmentioning

confidence: 99%

“…Compound 15 had indicated that substitution next to the hydrolytically displaced nitrogen atom of the departing amine was tolerated. The bridged piperazine proposed, in what was finally identified as the nominated chemical probe 16 12 (PFI-3, Scheme 2), conferred significantly enhanced chemical stability over the earlier prototype 11 .…”

Section: Resultsmentioning

confidence: 99%

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Identification of a Chemical Probe for Family VIII Bromodomains through Optimization of a Fragment Hit

et al. 2016

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The acetyl post-translational modification of chromatin at selected histone lysine residues is interpreted by an acetyl-lysine specific interaction with bromodomain reader modules. Here we report the discovery of the potent, acetyl-lysine competitive and cell active inhibitor PFI-3 that binds to certain Family VIII bromodomains while displaying significant, broader bromodomain family selectivity. The high specificity of PFI-3 for Family VIII was achieved through a novel bromodomain binding mode of a phenolic head group that led to the unusual displacement of water molecules that are generally retained by most other bromodomain inhibitors reported to date. The medicinal chemistry program that led to PFI-3 from an initial fragment screening hit is described in detail and additional analogues with differing Family VIII bromodomain selectivity profiles are also reported. We also describe the full pharmacological characterization of PFI-3 as a chemical probe, along with phenotypic data on adipocyte and myoblast cell differentiation assays.

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Chemische Epigenetik: der Einfluss chemischer und chemo‐biologischer Techniken auf die Zielstruktur‐Validierung von Bromodomänen

Schiedel¹,

Moroglu²,

Ascough³

et al. 2019

Angewandte Chemie

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Viele Disziplinen befassen sich gegenwärtig mit Epigenetik, da diese von Bedeutung für viele biologische Vorgänge und pathologische Zustände ist. Auf molekularer Ebene fußen epigenetische Prozesse auf Modifizierungen in Nukleinbasen der DNA und RNA und/oder posttranslationalen Modifizierungen (PTMs) von Histonproteinen. Die Hinweise mehren sich, dass diese Modifikationen einer dynamischen Regulation unterliegen, mit einer zum Teil bereits identifizierten zellulären Maschinerie, die der Modulation und Interpretation dieser Markierungen dient. Wir konzentrieren uns hier auf Bromodomänen, die an acetylierte Lysinreste (KAc) binden. Fortschritte auf dem Gebiet der Bromodomänen und ihrer Liganden werden von vielen Disziplinen beflügelt, wobei der Chemie und der chemischen Biologie eine besondere Rolle zukommt. Hier werden die chemischen und chemo‐biologischen Schlüsseltechniken diskutiert, mit deren Hilfe Bromodomänen erforscht und Liganden der Bromodomänen entwickelt werden konnten – unabdingbare Voraussetzungen für die Validierung der Bromodomäne als therapeutisch sinnvolle Zielstruktur.

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Selective targeting of the BRG/PB1 bromodomains impairs embryonic and trophoblast stem cell maintenance

Abstract: PFI-3, a novel inhibitor targeting the bromodomains of essential components of the BAF/PBAF complex, affects the differentiation of ESC and TSC.

Cited by 117 publications

References 55 publications

Large-scale analysis of water stability in bromodomain binding pockets with grand canonical Monte Carlo

Large-scale analysis of water stability in bromodomain binding pockets with grand canonical Monte Carlo

Identification of a Chemical Probe for Family VIII Bromodomains through Optimization of a Fragment Hit

Chemische Epigenetik: der Einfluss chemischer und chemo‐biologischer Techniken auf die Zielstruktur‐Validierung von Bromodomänen

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