Synthesis and Biological Investigation of (+)-JD1, an Organometallic BET Bromodomain Inhibitor,Organometallics

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Synthesis and Biological Investigation of (+)-JD1, an Organometallic BET Bromodomain Inhibitor
Organometallics ( IF 2.5 ) Pub Date : 2019-12-17 , DOI: 10.1021/acs.organomet.9b00750
Storm Hassell-Hart ₁ , Andrew Runcie ₂ , Tobias Krojer ₃ , Jordan Doyle ₁ , Ella Lineham ₄ , Cory A. Ocasio ₁ , Brenno A. D. Neto ₅ , Oleg Fedorov ₃ , Graham Marsh ₆ , Hannah Maple ₆ , Robert Felix ₆ , Rebecca Banks ₆ , Alessio Ciulli ₂ , Sarah Picaud ₃ , Panagis Filippakopoulos ₃ , Frank von Delft ₇ , Paul Brennan ₃ , Helen J. S. Stewart ₈ , Timothy J. Chevassut ₈ , Martin Walker ₉ , Carol Austin ₉ , Simon Morley ₄ , John Spencer ₁

Affiliation

Chemistry Department, School of Life Sciences, University of Sussex, Brighton BN1 9QJ, U.K.
Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, James Black Centre, Dow Street, Dundee DD1 5EH Scotland, U.K.
Structural Genomics Consortium (SGC), University of Oxford, Oxford OX3 7DQ, U.K.
Biochemistry Department, School of Life Sciences, University of Sussex, Brighton BN1 9QQ, U.K.
Laboratory of Medicinal and Technological Chemistry, University of Brasília, Chemistry Institute (IQ-UnB), Campus Universitário Darcy Ribeiro, Brasília, Q3 Distrito Federal 70904-970, Brazil
Bio-Techne (Tocris), The Watkins Building, Atlantic Road, Avonmouth, Bristol BS11 9QD, U.K.
Diamond Light Source (DLS), Harwell Science and Innovation Campus, Didcot OX11 0DE, U.K.
Brighton and Sussex Medical School, University of Sussex, Brighton BN1 9PS, U.K.
Eurofins Integrated Discovery UK Ltd., Fyfield Business & Research Park, Fyfield Road, Ongar, Essex CM5 0GS, U.K.

(+)-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 μM concentration, (+)-JD1 was able to inhibit c-Myc, a key driver in cancer and an indirect target of BRD4.

中文翻译：

有机金属BET溴结构域抑制剂（+）-JD1的合成和生物学研究

（+）-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，已经在生物物理，基于细胞的测定以及药代动力学研究中进行了合成和评估。它显示出对BRD亚型的纳摩尔活性，并与BRD4的第一个溴结构域复合确定了其共晶体结构，并与已知的BRD4小分子探针（+）-JQ1进行了比较。在1μM的浓度下，（+）-JD1能够抑制c-Myc，c-Myc是癌症的关键驱动器，也是BRD4的间接靶标。

更新日期：2019-12-18

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