The bromodomain and extra-terminal (BET) family proteins, which are involved in chromatin function, have been shown to be promising drug targets in several pathological conditions, including cancer and inflammation. There is considerable interest in the development of BET inhibitors with novel scaffolds to modulate the epigenesis of such diseases. Here, high-resolution crystal structures of the purine class of FDA-approved drugs (theophylline, doxophylline and acyclovir) and non-FDA-approved compounds (3-methyl-7-propylxanthine and theobromine) complexed with hBRD2 bromodomains BD1 and BD2 are reported. Remarkably, a new binding site is exhibited by stacking the compounds against the WPF shelf of BD1 and BD2. This serendipitous binding, in addition to the known acetyl-lysine binding site, sufficiently anchors the ligands in the solvent-exposed region. In addition, slight variations in the lipophilicity of these molecules significantly affected the in vitro binding affinity and selectivity towards BD1 compared with BD2. This idiosyncratic binding provides a new structural framework to link these sites for the development of next-generation inhibitors of the BET family.

中文翻译：

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对 hBRD2 中嘌呤药物分子的结构和生化见解描绘了一种独特的结合模式，为 BET 家族抑制剂的设计开辟了新前景

参与染色质功能的溴结构域和额外末端 (BET) 家族蛋白已被证明是多种病理状况（包括癌症和炎症）中有希望的药物靶点。人们对开发具有新型支架的 BET 抑制剂来调节此类疾病的后生具有很大的兴趣。在此，报告了 FDA 批准的嘌呤类药物（茶碱、多索茶碱和阿昔洛韦）和非 FDA 批准的化合物（3-甲基-7-丙基黄嘌呤和可可碱）与 hBRD2 溴结构域 BD1 和 BD2 复合的高分辨率晶体结构。值得注意的是，通过将化合物堆叠在 BD1 和 BD2 的 WPF 架上，展示了一个新的结合位点。除了已知的乙酰基-赖氨酸结合位点之外，这种偶然的结合足以将配体锚定在溶剂暴露区域中。此外，与 BD2 相比，这些分子亲脂性的微小变化显着影响了BD1 的体外结合亲和力和选择性。这种特殊的结合提供了一个新的结构框架来连接这些位点，用于开发 BET 家族的下一代抑制剂。