Fragment-Based Discovery of Bromodomain Inhibitors Part 2: Optimization of Phenylisoxazole Sulfonamides
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- 作者：Paul Bamborough ; Hawa Diallo ; Jonathan D. Goodacre ; Laurie Gordon ; Antonia Lewis ; Jonathan T. Seal ; David M. Wilson ; Michael D. Woodrow ; Chun-wa Chung
- 刊名：Journal of Medicinal Chemistry
- 出版年：2012
- 出版时间：January 26, 2012
- 年：2012
- 卷：55
- 期：2
- 页码：587-596
- 全文大小：773K
- 年卷期：v.55,no.2(January 26, 2012)
- ISSN：1520-4804
文摘
Bromodomains are epigenetic reader modules that regulate gene transcription through their recognition of acetyl-lysine modified histone tails. Inhibitors of this protein鈥損rotein 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.