A poised fragment library enables rapid synthetic expansion yielding the first reported inhibitors of PHIP(2), an atypical bromodomain

Cox, Oakley Benjamin; Krojer, T.; Collins, P.; Monteiro, Octovia; Talon, R.; Bradley, A.R.; Fedorov, O.; Amin, Jahangir; Marsden, Brian D.; Spencer, John; Delft, Frank von; Brennan, P.E.

doi:10.1039/c5sc03115j

Cited by 144 publications

(160 citation statements)

References 37 publications

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“…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 . In the fragment screen that discovered a number of BRPF1B binders 15 , only fragment 5 (1-isoquinolinone; Protein Data Bank (PDB)-ID 5C87) out of 19 ligands displaced W1.…”

Section: General Approachmentioning

confidence: 99%

“…In the fragment screen that discovered a number of BRPF1B binders 15 , only fragment 5 (1-isoquinolinone; Protein Data Bank (PDB)-ID 5C87) out of 19 ligands displaced W1. In the fragment screen that identified four hits for the atypical bromodomain PHIP(2) 14 , only one (a thiourea; PDB-ID 5ENB) displaced W1. In both cases, the displacement did not result in higher affinities when compared to other hits.…”

Section: General Approachmentioning

confidence: 99%

“…For instance, Harner et al 9 found that an aminotetrahydrothiazole fragment could displace W4 from ATAD2. Cox et al 14 noticed the displacement of W1 from the binding pocket of PHIP(2) (in Family III) by a thiourea fragment, while Zhu and Caflisch 15 reported the displacement of W1 from BRPF1 (a member of Family IV) by an isoquinolinone fragment. Recently, Crawford et al 16 described the discovery of ligands causing a rearrangement of the water network in BRD4(1) and TAF1 (2) and the displacement of W3 and W4.…”

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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 Approachmentioning

confidence: 99%

Section: General Approachmentioning

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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“…Pan-bromodomain inhibitors such as bromosporine and [1,2,4]triazolo[4,3-a] phthalazines have demonstrated inhibitory activity for many different bromodomains (46,47). Their promiscuity suggests that they may be of limited value in the clinic, but these compounds represent useful tools in dissecting bromodomain function in many organisms.…”

Section: Development Of Bromodomain Inhibitorsmentioning

confidence: 99%

Bromodomains in Protozoan Parasites: Evolution, Function, and Opportunities for Drug Development

Jeffers

Yang

Huang

et al. 2017

Microbiol Mol Biol Rev

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SUMMARY Parasitic infections remain one of the most pressing global health concerns of our day, affecting billions of people and producing unsustainable economic burdens. The rise of drug-resistant parasites has created an urgent need to study their biology in hopes of uncovering new potential drug targets. It has been established that disrupting gene expression by interfering with lysine acetylation is detrimental to survival of apicomplexan (Toxoplasma gondii and Plasmodium spp.) and kinetoplastid (Leishmania spp. and Trypanosoma spp.) parasites. As “readers” of lysine acetylation, bromodomain proteins have emerged as key gene expression regulators and a promising new class of drug target. Here we review recent studies that demonstrate the essential roles played by bromodomain-containing proteins in parasite viability, invasion, and stage switching and present work showing the efficacy of bromodomain inhibitors as novel antiparasitic agents. In addition, we performed a phylogenetic analysis of bromodomain proteins in representative pathogens, some of which possess unique features that may be specific to parasite processes and useful in future drug development.

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“…Weiterentwicklungen der Leitstruktur zielten auf die Konvertierung des potentiell labilen Methylesters in Molekül 1 zu einem Substituenten ab,d er bei idealerweise gleichbleibender Aktivitäte inen Vektor fürd ie Identifizierung neuer Binde-Interaktionen bieten würde.Ineiner "bereiten" (poised) Herangehensweise [28] wurde Molekül 1 in Synthons zur schnellen Diversifizierung zerlegt (Abbildung 3). Untersuchung der Struktur-Wirkungsbeziehung an Molekül 1 führten zur Synthese von über 200 Analoga (ausgewählte Beispiele in Tabelle 1, weitere in den Hintergrundinformationen).…”

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Entdeckung einer chemischen Sonde für MLLT1/3‐YEATS‐Domänen

et al. 2018

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YEATS-Domänen(YD)-enthaltende Proteine sind eine neue Klasse epigenetischer Zielstrukturen fürd ie Wirkstoffentwicklung. Die YD-enthaltenden Proteine MLLT1 (ENL/YEATS1) und MLLT3 (AF9/MLLT3) sind oft in Krebs dereguliert und wurden daher als potentielle Zielstrukturen für neue Therapieansätzed iskutiert. Wir berichten hier die Entwicklung und Charakterisierung des ersten niedermolekularen Inhibitors der YD in MLLT1 und MLLT3, SGC-iMLLT.E r ist ein potenter und selektiver Inhibitor der MLLT1/3-Histon-Interaktion und zeichnet sich durch exzellente Selektivitätg egenüber anderen menschlichen YD-Proteinen (YEATS2/4) und Bromodomänen aus.A ufgrund der zellulären Aktivität eignet sich die entwickelte chemische Sonde um die biologi-schenFunktionen der YD in MLLT1/3 und das therapeutische Potential dieser kleinen Proteininteraktionsdomänen zu verstehen. Lysin-Seitenketten mit Acetyl(Kac)-oder Crotonyl(Kcr)-Modifikation sind grundlegende Bestandteile des sog. epigenetischen Codes. [1,2] Neben den bekannten Acyl-Lysin-bindenden Bromodomänen [3,4] binden YEATS(YAF9, ENL, AF9, TAF14, SAS5)-Domänen-enthaltende Proteine sowohl Acetyl-Lysin als auch Crotonyl-Lysin-enthaltende Sequenzen. Neuere Berichte suggerierten, dass Dysregulation von YEATS-Domänen(YD)-enthaltenden Proteinen mit der Entstehung und des Fortschreitens einiger Krebsvarianten korreliert. [5][6][7] Im Menschen werden vier YD-Proteine (MLLT1, YEATS2, MLLT3 und YEATS4) exprimiert. Tr otz hoher Sequenzhomologie (88 %i nd er YD) und einer ähnlichen Rolle bezüglich Komplexformierung,s cheinen MLLT1 und MLLT3 unabhängige Rollen in akuter myeloischer Leukämie (AML) zu haben. [5,6] MLLT1 assoziiert mit DOT1L, [8][9][10] steht im Fall von Mutationen der YD in Verbindung mit der Entwicklung von Wilms-Tumoren. [11] In Leukämie assoziiert MLLT1 mit dem wachstumsfçrdernden Protein AF4. [12] MLLT3 ist Teil des sogenannten super Elongationskomplex (SEC) [7] und ist im Gegensatz zu MLLT1 der häufigste Fusionpartner von MLL (mixed lineage leukaemia protein) in AML (ca. 30 %d er Fälle). [7] Jüngst wurde fürMLLT1/3 eine "KILK"-Motiv-Interaktion gezeigt, ebenfalls in der extra-terminalen (ET) Domäne von BRD3, die zur Rekrutierung von Chromatin-Remodellierungskomplexen wie NuRD,B AF und INO80 führt. [13] Obwohl YD auch in weiteren Krankheiten eine Rolle spielen, [7] wurden bisher keine Inhibitoren in Form von kleinen organischen Molekülen entwickelt, die das Verständnis des biologischen Kontexts der YD vorantreiben kçnnten.

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A poised fragment library enables rapid synthetic expansion yielding the first reported inhibitors of PHIP(2), an atypical bromodomain

Abstract: High concentration crystal soaking of poised fragments and one-step elaboration identified compound 17 as an inhibitor of the PHIP(2) bromodomain.

Cited by 144 publications

References 37 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

Bromodomains in Protozoan Parasites: Evolution, Function, and Opportunities for Drug Development

Entdeckung einer chemischen Sonde für MLLT1/3‐YEATS‐Domänen

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