BET 溴结构域配体：探测 WPF 支架以提高 BRD4 溴结构域亲和力和代谢稳定性。
BET bromodomain ligands: Probing the WPF shelf to improve BRD4 bromodomain affinity and metabolic stability.
机构信息
Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, United Kingdom.
Nuffield Department of Clinical Medicine, Structural Genomics Consortium, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 3TA, United Kingdom.
出版信息
Bioorg Med Chem. 2018 Jul 15;26(11):2937-2957. doi: 10.1016/j.bmc.2018.05.003. Epub 2018 May 15.
Ligands for the bromodomain and extra-terminal domain (BET) family of bromodomains have shown promise as useful therapeutic agents for treating a range of cancers and inflammation. Here we report that our previously developed 3,5-dimethylisoxazole-based BET bromodomain ligand (OXFBD02) inhibits interactions of BRD4(1) with the RelA subunit of NF-κB, in addition to histone H4. This ligand shows a promising profile in a screen of the NCI-60 panel but was rapidly metabolised (t = 39.8 min). Structure-guided optimisation of compound properties led to the development of the 3-pyridyl-derived OXFBD04. Molecular dynamics simulations assisted our understanding of the role played by an internal hydrogen bond in altering the affinity of this series of molecules for BRD4(1). OXFBD04 shows improved BRD4(1) affinity (IC = 166 nM), optimised physicochemical properties (LE = 0.43; LLE = 5.74; SFI = 5.96), and greater metabolic stability (t = 388 min).
溴结构域和末端结构域（BET）家族的配体已被证明是治疗多种癌症和炎症的有用治疗剂。在这里，我们报告了我们之前开发的基于 3,5-二甲基异恶唑的 BET 溴结构域配体（OXFBD02），除了组蛋白 H4 之外，还可以抑制 BRD4(1)与 NF-κB 的 RelA 亚基的相互作用。该配体在 NCI-60 小组的筛选中表现出有希望的特征，但被迅速代谢（t=39.8min）。化合物性质的结构导向优化导致了 3-吡啶衍生的 OXFBD04 的开发。分子动力学模拟有助于我们理解内部氢键在改变该系列分子与 BRD4(1)亲和力方面的作用。OXFBD04 显示出改善的 BRD4(1)亲和力（IC=166nM）、优化的理化性质（LE=0.43；LLE=5.74；SFI=5.96）和更高的代谢稳定性（t=388min）。
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