LP99: Discovery and Synthesis of the First Selective BRD7/9 Bromodomain Inhibitor
LP99: Discovery and Synthesis of the First Selective BRD7/9 Bromodomain Inhibitor
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DOI：
10.1002/anie.201501394
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发表时间：
2015-05-18
影响因子：
16.6
通讯作者：
Dixon, Darren J.
中科院分区：
文献类型：
--
作者：
Clark, Peter G. K.;Vieira, Lucas C. C.;Dixon, Darren J.
含溴结构域蛋白BRD 9和BRD 7是人SWI/SNF染色质重塑复合物BAF和PBAF的一部分。迄今为止，尚未报道BRD 7/9的选择性抑制剂，尽管其作为生物学工具或作为未来治疗的先导的潜在价值。喹诺酮稠合内酰胺LP 99现在被报道为BRD 7和BRD 9溴结构域的第一个有效和选择性抑制剂。通过平衡基于结构的抑制剂设计和生物物理表征与易处理的化学合成来加速从片段命中开发LP 99：复杂性构建硝基-曼尼希/内酰胺化级联过程允许早期结构-活性关系研究，而对映体选择性有机催化硝基-曼尼希反应使得能够以对映体富集形式和规模合成先导支架。这种表观遗传探针显示出抑制BRD 7和BRD 9与体外和细胞中的乙酰化组蛋白的缔合。此外，使用LP 99来证明BRD 7/9在调节促炎细胞因子分泌中起作用。
The bromodomain-containing proteins BRD9 and BRD7 are part of the human SWI/SNF chromatin-remodeling complexes BAF and PBAF. To date, no selective inhibitor for BRD7/9 has been reported despite its potential value as a biological tool or as a lead for future therapeutics. The quinolone-fused lactam LP99 is now reported as the first potent and selective inhibitor of the BRD7 and BRD9 bromodomains. Development of LP99 from a fragment hit was expedited through balancing structure-based inhibitor design and biophysical characterization against tractable chemical synthesis: Complexity-building nitro-Mannich/lactamization cascade processes allowed for early structure-activity relationship studies whereas an enantioselective organocatalytic nitro-Mannich reaction enabled the synthesis of the lead scaffold in enantioenriched form and on scale. This epigenetic probe was shown to inhibit the association of BRD7 and BRD9 to acetylated histones invitro and in cells. Moreover, LP99 was used to demonstrate that BRD7/9 plays a role in regulating pro-inflammatory cytokine secretion.