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

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posted on 2023-06-09, 23:01 authored by Storm Hassell-HartStorm Hassell-Hart, Sarah Picaud, Raphael Lengacher, Joshua Csucker, Regis Millet, Gilles Gasser, Roger Alberto, Hannah Maple, Robert Felix, Zbigniew J Lesnikowski, Helen Stewart, Timothy ChevassutTimothy Chevassut, Simon Morley, Panagis Filippakopoulos, John SpencerJohn Spencer
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 KD=ca. 130 nm vs. BRD4(1) and a ca. 2-fold selectivity over BRD4(2) (KD=ca. 260 nm). Its binding to the first bromodomain of BRD4 was determined by a protein cocrystal structure.

Funding

Poised Fragment Libraries for Atypical Bromodomain Inhibition; G2210; EPSRC-ENGINEERING & PHYSICAL SCIENCES RESEARCH COUNCIL; EP/P026990/1

History

Publication status

  • Published

File Version

  • Accepted version

Journal

Helvetica Chimica Acta

ISSN

0018-019X

Publisher

Wiley

Issue

3

Volume

104

Page range

1-7

Article number

a2000214

Department affiliated with

  • Clinical and Experimental Medicine Publications

Full text available

  • Yes

Peer reviewed?

  • Yes

Legacy Posted Date

2021-02-11

First Open Access (FOA) Date

2022-01-28

First Compliant Deposit (FCD) Date

2021-02-11

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