Structure-Based Design of Highly Selective Inhibitors of the CREB Binding Protein Bromodomain,Journal of Medicinal Chemistry

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Structure-Based Design of Highly Selective Inhibitors of the CREB Binding Protein Bromodomain
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-05-12 00:00:00 , DOI: 10.1021/acs.jmedchem.6b01839
R. Aldrin Denny ₁ , Andrew C. Flick ₂ , Jotham Coe ₂ , Jonathan Langille , Arindrajit Basak ₂ , Shenping Liu ₃ , Ingrid Stock ₄ , Parag Sahasrabudhe ₃ , Paul Bonin ₄ , Duncan A. Hay _{5,

6} , Paul E. Brennan ₆ , Mathew Pletcher ₇ , Lyn H. Jones ₁ , Eugene L. Piatnitski Chekler ₁

Affiliation

Chemical probes are required for preclinical target validation to interrogate novel biological targets and pathways. Selective inhibitors of the CREB binding protein (CREBBP)/EP300 bromodomains are required to facilitate the elucidation of biology associated with these important epigenetic targets. Medicinal chemistry optimization that paid particular attention to physiochemical properties delivered chemical probes with desirable potency, selectivity, and permeability attributes. An important feature of the optimization process was the successful application of rational structure-based drug design to address bromodomain selectivity issues (particularly against the structurally related BRD4 protein).

中文翻译：

CREB结合蛋白溴结构域的高选择性抑制剂的基于结构的设计。

临床前靶标验证需要化学探针，以探询新的生物学靶标和途径。需要CREB结合蛋白（CREBBP）/ EP300溴结构域的选择性抑制剂，以促进阐明与这些重要表观遗传学靶标相关的生物学。特别关注物化性质的药物化学优化为化学探针提供了理想的效价，选择性和渗透性属性。优化过程的重要特征是成功应用基于合理结构的药物设计来解决溴结构域选择性问题（尤其是针对与结构相关的BRD4蛋白）。

更新日期：2017-05-12

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