Synthesis and biological investigation of (+)-JD1, an organometallic BET bromodomain inhibitor

Hassell-Hart, Storm, Runcie, Andrew, Krojer, Tobias, Doyle, Jordan, Lineham, Ella, Ocasio, Cory A, Neto, Brenno A D, Fedorov, Oleg, Marsh, Graham, Maple, Hannah, Felix, Robert, Banks, Rebecca, Ciulli, Alessio, Picaud, Sarah, Filippakopoulos, Panagis, von Delft, Frank, Brennan, Paul, Stewart, Helen J S, Chevassut, Timothy J, Walker, Martin, Austin, Carol, Morley, Simon and Spencer, John (2019) Synthesis and biological investigation of (+)-JD1, an organometallic BET bromodomain inhibitor. Organometallics. ISSN 0276-7333

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Abstract

(+)-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.

Item Type: Article
Schools and Departments: School of Life Sciences > Biochemistry
School of Life Sciences > Chemistry
Subjects: Q Science > QD Chemistry
Q Science > QD Chemistry > QD0241 Organic chemistry
Q Science > QD Chemistry > QD0241 Organic chemistry > QD0411 Organometallic chemistry and compounds
Q Science > QD Chemistry > QD0901 Crystallography
Depositing User: John Spencer
Date Deposited: 19 Dec 2019 08:53
Last Modified: 19 Dec 2019 09:00
URI: http://sro.sussex.ac.uk/id/eprint/88904

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Project NameSussex Project NumberFunderFunder Ref
Poised Fragment Libraries for Atypical Bromodomain InhibitionG2210EPSRC-ENGINEERING & PHYSICAL SCIENCES RESEARCH COUNCILEP/P026990/1