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

Hassell-Hart, Storm, Picaud, Sarah, Lengacher, Raphael, Csucker, Joshua, Millet, Regis, Gasser, Gilles, Alberto, Roger, Maple, Hannah, Felix, Robert, Leśnikowski, Zbigniew J, Stewart, Helen J S, Chevassut, Timothy J, Morley, Simon, Filippakopoulos, Panagis and Spencer, John (2021) Probing BRD inhibition substituent effects in bulky analogues of (+)-JQ1. Helvetica Chimica Acta, 104 (3). a2000214 1-7. ISSN 0018-019X

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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[,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.

Item Type: Article
Schools and Departments: Brighton and Sussex Medical School > Clinical and Experimental Medicine
School of Life Sciences > Chemistry
SWORD Depositor: Mx Elements Account
Depositing User: Mx Elements Account
Date Deposited: 11 Feb 2021 08:25
Last Modified: 28 Feb 2022 12:15

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Project NameSussex Project NumberFunderFunder Ref
Poised Fragment Libraries for Atypical Bromodomain InhibitionG2210EPSRC-ENGINEERING & PHYSICAL SCIENCES RESEARCH COUNCILEP/P026990/1