Selective Fragments for the CREBBP Bromodomain Identified from an Encoded Self-assembly Chemical Library.,ChemMedChem

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Selective Fragments for the CREBBP Bromodomain Identified from an Encoded Self-assembly Chemical Library.
ChemMedChem ( IF 3.6 ) Pub Date : 2020-07-19 , DOI: 10.1002/cmdc.202000528
Marco Catalano ₁ , Mustafa Moroglu ₂ , Petra Balbi ₁ , Federica Mazzieri ₁ , James Clayton ₂ , Katrina H Andrews ₂ , Martina Bigatti ₃ , Jörg Scheuermann ₁ , Stuart J Conway ₂ , Dario Neri ₁

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DNA‐encoded chemical libraries (DECLs) are collections of chemical moieties individually coupled to distinctive DNA barcodes. Compounds can be displayed either at the end of a single DNA strand (i. e., single‐pharmacophore libraries) or at the extremities of two complementary DNA strands (i. e., dual‐pharmacophore libraries). In this work, we describe the use of a dual‐pharmacophore encoded self‐assembly chemical (ESAC) library for the affinity maturation of a known 4,5‐dihydrobenzodiazepinone ring (THBD) acetyl‐lysine (KAc) mimic for the cyclic‐AMP response element binding protein (CREB) binding protein (CREBBP or CBP) bromodomain. The new pair of fragments discovered from library selection showed a sub‐micromolar affinity for the CREBBP bromodomain in fluorescence polarization and ELISA assays, and selectivity against BRD4(1).

中文翻译：

从编码自组装化学库中识别的 CREBBP Bromodomain 的选择性片段。

DNA 编码的化学文库 (DECL) 是单独耦合到独特 DNA 条形码的化学部分的集合。化合物可以展示在单条 DNA 链的末端（即单药团库），也可以展示在两条互补 DNA 链的末端（即双药团库）。在这项工作中，我们描述了使用双药基编码的自组装化学物质 (ESAC) 库来使已知的 4,5-二氢苯二氮杂酮环 (THBD) 乙酰赖氨酸 (KAc) 模拟物用于环 AMP 的亲和力成熟反应元件结合蛋白 (CREB) 结合蛋白（CREBBP 或 CBP）溴结构域。从文库选择中发现的新片段对在荧光偏振和 ELISA 测定中显示出对 CREBBP 溴结构域的亚微摩尔亲和力，以及对 BRD4(1) 的选择性。

更新日期：2020-09-14

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