Synthesis and Biological Investigation of (+)-JD1, an Organometallic BET Bromodomain Inhibitor
Synthesis and Biological Investigation of (+)-JD1, an Organometallic BET Bromodomain Inhibitor
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DOI：
10.1021/acs.organomet.9b00750
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发表时间：
2020-02-10
期刊：
影响因子：
2.8
通讯作者：
Spencer, John
中科院分区：
文献类型：
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作者：
Hassell-Hart, Storm;Runcie, Andrew;Spencer, John
(+)-JD1 是 BET 溴结构域 (BRD) 探针分子 (+)-JQ1 的合理设计的二茂铁类似物，已在生物物理、基于细胞的测定以及药代动力学研究中进行合成和评估。它表现出针对 BRD 同种型的纳摩尔活性，其共晶结构是与 BRD4 的第一个溴结构域复合物确定的，并与 (+)-JQ1（一种已知的 BRD4 小分子探针）的共晶结构进行比较。在 1 μM 浓度下，(+)-JD1 能够抑制 c-Myc，c-Myc 是癌症的关键驱动因素，也是 BRD4 的间接靶标。
(+)-JD1, a rationally designed ferrocene analogue of the BET bromodomain (BRD) probe molecule (+)-JQ1, has been synthesized and evaluated in biophysical, cell-based assays as well as in pharmacokinetic studies. It displays nanomolar activity against BRD isoforms, and its cocrystal structure was determined in complex with the first bromodomain of BRD4 and compared with that of (+)-JQ1, a known BRD4 small-molecule probe. At 1 mu M concentration, (+)-JD1 was able to inhibit c-Myc, a key driver in cancer and an indirect target of BRD4.