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Synthesis and biological investigation of (+)-JD1, an organometallic BET bromodomain inhibitor
DOI:
10.1021/acs.organomet.9b00750
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
Added On:
06/01/2020 11:47
Discipline Tags:
Non-Communicable Diseases
Health & Wellbeing
Cancer
Biochemistry
Chemistry
Structural biology
Life Sciences & Biotech
Organometallic Chemistry
Technical Tags:
Diffraction
Macromolecular Crystallography (MX)