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Probing BRD inhibition substituent effects in bulky analogues of (+)‐JQ1probing substituent effects in bulky analogues of (+)‐JQ1

DOI: 10.1002/hlca.202000214 DOI Help

Authors: John Spencer (University of Sussex) , Storm Hassell (University of Sussex) , Sarah Picaud (Structural Genomics Consortium, University of Oxford) , Ralph Lengacher (University of Zurich) , Joshua Csuker (University of Zurich) , Regis Millet (Universite de Lille) , Gilles Gasser (Chimie ParisTech) , Roger Alberto (University of Zurich) , Hannah Maple (Tocris) , Robert Felix (Tocris) , Zbigniew Leśnikowski (Polska Akademia Nauk Instytut Informatyki Teoretycznej i Stosowanej) , Helen Stewart (Brighton and Sussex Medical School) , Timothy Chevassut (Brighton and Sussex Medical School) , Simon Morley (University of Sussex) , Panagis Filippakopoulos (Structural Genomics Consortium, University of Oxford)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Helvetica Chimica Acta

State: Published (Approved)
Published: January 2021
Diamond Proposal Number(s): 19301

Abstract: A series of bulky organometallic and organic analogues of the bromodomain (BRD) inhibitor (+)‐JQ1 have been prepared. The most potent, N‐[(adamantan‐1‐yl)methyl]‐2‐[(9S)‐7‐(4‐chlorophenyl)‐4,5,13‐trimethyl‐3‐thia‐1,8,11,12‐tetraazatricyclo[8.3.0.02,6]trideca‐2(6),4,7,10,12‐pentaen‐9‐yl]acetamide, 2e , showed excellent potency with an K D = ca. 130 nM vs BRD4(1) and a ca. 2‐fold selectivity over BRD4(2) (K D = ca. 260 nM). Its binding to the first bromodomain of BRD4 was determined by a protein cocrystal structure.

Journal Keywords: Cancer; epigenetics; bioorganometallic chemistry; bromodomain; benzodiazepines

Diamond Keywords: Epigenetics

Subject Areas: Chemistry, Biology and Bio-materials


Instruments: I03-Macromolecular Crystallography

Added On: 02/02/2021 15:31

Discipline Tags:

Organic Chemistry Life Sciences & Biotech Health & Wellbeing Cancer Non-Communicable Diseases Structural biology Chemistry Biochemistry

Technical Tags:

Diffraction Macromolecular Crystallography (MX)