Fragment-Based Discovery of Bromodomain Inhibitors Part 2: Optimization of Phenylisoxazole Sulfonamides
Fragment-Based Discovery of Bromodomain Inhibitors Part 2: Optimization of Phenylisoxazole Sulfonamides
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DOI：
10.1021/jm201283q
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发表时间：
2012-01-26
影响因子：
7.3
通讯作者：
Chung, Chun-wa
中科院分区：
文献类型：
--
作者：
Bamborough, Paul;Diallo, Hawa;Chung, Chun-wa
溴结构域是表观遗传解读模块，通过识别乙酰赖氨酸修饰的组蛋白尾部来调节基因转录。这种蛋白-蛋白相互作用的抑制剂具有调节多种疾病的潜力，最近披露的一类BET化合物具有深刻的抗炎和抗增殖作用。虽然这些化合物是通过表型分析发现的，但在这里，我们提出了一种高效的替代方法来寻找新的化学模板，利用丰富的结构知识，存在于这个目标类。通过基于结构的设计，通过聚焦片段筛选产生的苯二甲基异恶唑化学型迅速优化，导致磺胺系列在细胞分析中显示出抗炎活性。这个原理验证实验证明了BET家族和溴域目标类对基于片段的命中发现和基于结构的先导优化的可追溯性。
Bromodomains are epigenetic reader modules that regulate gene transcription through their recognition of acetyl-lysine modified histone tails. Inhibitors of this protein-protein interaction have the potential to modulate multiple diseases as demonstrated by the profound anti-inflammatory and antiproliferative effects of a recently disclosed class of BET compounds. While these compounds were discovered using phenotypic assays, here we present a highly efficient alternative approach to find new chemical templates, exploiting the abundant structural knowledge that exists for this target class. A phenyl dimethyl isoxazole chemotype resulting from a focused fragment screen has been rapidly optimized through structure-based design, leading to a sulfonamide series showing anti-inflammatory activity in cellular assays. This proof-of-principle experiment demonstrates the tractability of the BET family and bromodomain target class to fragment-based hit discovery and structure-based lead optimization.