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Fragment-Based Discovery of Low-Micromolar ATAD2 Bromodomain Inhibitors.

Fragment-Based Discovery of Low-Micromolar ATAD2 Bromodomain Inhibitors.

Journal of medicinal chemistry (2015-07-15)

Emmanuel H Demont, Chun-wa Chung, Rebecca C Furze, Paola Grandi, Anne-Marie Michon, Chris Wellaway, Nathalie Barrett, Angela M Bridges, Peter D Craggs, Hawa Diallo, David P Dixon, Clement Douault, Amanda J Emmons, Emma J Jones, Bhumika V Karamshi, Kelly Locke, Darren J Mitchell, Bernadette H Mouzon, Rab K Prinjha, Andy D Roberts, Robert J Sheppard, Robert J Watson, Paul Bamborough

ABSTRACT

Overexpression of ATAD2 (ATPase family, AAA domain containing 2) has been linked to disease severity and progression in a wide range of cancers, and is implicated in the regulation of several drivers of cancer growth. Little is known of the dependence of these effects upon the ATAD2 bromodomain, which has been categorized as among the least tractable of its class. The absence of any potent, selective inhibitors limits clear understanding of the therapeutic potential of the bromodomain. Here, we describe the discovery of a hit from a fragment-based targeted array. Optimization of this produced the first known micromolar inhibitors of the ATAD2 bromodomain.

MATERIALS

Product Number

Brand

Product Description

Sigma-Aldrich

Ethanolamine, ACS reagent, ≥99.0%

Sigma-Aldrich

Sodium chloride-³⁵Cl, 99 atom % ³⁵Cl

Sigma-Aldrich

Ethanolamine, purified by redistillation, ≥99.5%

Sigma-Aldrich

Sodium chloride solution, 0.85%

Sigma-Aldrich

Sodium chloride, random crystals, 99.9% trace metals basis

Sigma-Aldrich

Glycerol solution, 83.5-89.5% (T)

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Nitrilotriacetic acid, BioUltra, ≥99.0% (T)

Sigma-Aldrich

Trizma^® base, BioUltra, Molecular Biology, ≥99.8% (T)

Sigma-Aldrich

Sodium chloride solution, BioUltra, Molecular Biology, ~5 M in H₂O

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HEPES, BioUltra, Molecular Biology, ≥99.5% (T)

Sigma-Aldrich

DL-Dithiothreitol solution, BioUltra, Molecular Biology, ~1 M in H₂O

Sigma-Aldrich

Ethanolamine, ≥99%

Sigma-Aldrich

Trizma^® base, ≥99.0% (T)

Sigma-Aldrich

Nitrilotriacetic acid, ACS reagent, ≥99.0%

Sigma-Aldrich

Trizma^® base, 99.7% (T), puriss. p.a.

Sigma-Aldrich

Sodium chloride, BioUltra, Molecular Biology, ≥99.5% (AT)

Sigma-Aldrich

Phenylmethanesulfonyl fluoride, ≥99.0% (T)

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Tris(hydroxymethyl)aminomethane, ACS reagent, ≥99.8%

Sigma-Aldrich

Sodium chloride, AnhydroBeads^™, −10 mesh, 99.999% trace metals basis

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Protease Inhibitor Cocktail, for use with mammalian cell and tissue extracts, DMSO solution

Sigma-Aldrich

Trizma^® base, BioXtra, pH 10.5-12.0 (1 M in H₂O), ≥99.9% (titration)

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Tromethamine, meets USP testing specifications

Sigma-Aldrich

Ethanolamine, ≥98%

Sigma-Aldrich

2-Mercaptoethanol, Molecular Biology, suitable for electrophoresis, suitable for cell culture, BioReagent, 99% (GC/titration)

Sigma-Aldrich

2-Mercaptoethanol, ≥99.0%

Sigma-Aldrich

BIS-TRIS propane, BioPerformance Certified, suitable for cell culture, ≥99.0%

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Ampicillin, meets USP testing specifications

Sigma-Aldrich

Phenylmethanesulfonyl fluoride, ≥98.5% (GC)

Sigma-Aldrich

Nitrilotriacetic acid trisodium salt, Sigma Grade, ≥98%

Sigma-Aldrich

Sodium chloride solution, 5 M