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

DOI: 10.1021/acs.organomet.9b00750 DOI Help

Authors: Storm Hassell-hart (University of Sussex) , Andrew Runcie (University of Dundee) , Tobias Krojer (Structural Genomics Consortium (SGC), University of Oxford) , Jordan Doyle (University of Sussex) , Ella Lineham (University of Sussex) , Cory A. Ocasio (University of Sussex) , Brenno A. D. Neto (University of Brasília) , Oleg Fedorov (Structural Genomics Consortium (SGC), University of Oxford) , Graham Marsh (Bio-Techne (Tocris)) , Hannah Maple (Bio-Techne (Tocris)) , Robert Felix (Bio-Techne (Tocris)) , Rebecca Banks (Structural Genomics Consortium (SGC), University of Oxford) , Alessio Ciulli (University of Dundee) , Sarah Picaud (Structural Genomics Consortium, University of Oxford) , Panagis Filippakopoulos (Structural Genomics Consortium (SGC), University of Oxford) , Frank Von Delft (Diamond Light Source) , Paul Brennan (Structural Genomics Consortium (SGC), University of Oxford) , Helen J. S. Stewart (University of Sussex) , Timothy J. Chevassut (University of Sussex) , Martin Walker (Eurofins Integrated Discovery UK Ltd) , Carol Austin (Eurofins Integrated Discovery UK Ltd) , Simon Morley (University of Sussex) , John Spencer (University of Sussex)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Organometallics

State: Published (Approved)
Published: December 2019
Diamond Proposal Number(s): 19301

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.

Subject Areas: Chemistry, Biology and Bio-materials


Instruments: I03-Macromolecular Crystallography , I04-Macromolecular Crystallography

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