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

Storm Hassell-Hart, Andrew Runcie, Tobias Krojer, Jordan Doyle, Ella Lineham, Cory A. Ocasio, Brenno A. D. Neto, Oleg Fedorov, Graham Marsh, Hannah Maple, Robert Felix, Rebecca Banks, Alessio Ciulli, Sarah Picaud, Panagis Filippakopoulos, Frank Von Delft, Paul Brennan, Helen J. S. Stewart, Timothy J. Chevassut, Martin WalkerCarol Austin, Simon Morley, John Spencer

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
JournalOrganometallics
Early online date17 Dec 2019
DOIs
Publication statusE-pub ahead of print - 17 Dec 2019

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