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

PMID26155854

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

S0817

Sigma-Aldrich

Sodium chloride solution, 0.85%

411000

Sigma-Aldrich

Ethanolamine, purified by redistillation, ≥99.5%

378860

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12072

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Benzamidine, ≥95.0%

54457

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93352

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Trizma^® base, ≥99.0% (T)

72559

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Nitrilotriacetic acid, BioUltra, ≥99.0% (T)

72560

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Nitrilotriacetic acid, ACS reagent, ≥99.0%

63689

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2-Mercaptoethanol, BioUltra, Molecular Biology, ≥99.0% (GC)

93350

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

71386

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

N9877

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S1679

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H6147

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S8776

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S3014

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H7523

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S7653

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H4034

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S5886

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T6066

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T1503

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