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Probing BRD Inhibition Substituent Effects in Bulky Analogues of (+)‐JQ1
Author(s) -
HassellHart 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,
Spencer John
Publication year - 2021
Publication title -
helvetica chimica acta
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.74
H-Index - 82
eISSN - 1522-2675
pISSN - 0018-019X
DOI - 10.1002/hlca.202000214
Subject(s) - chemistry , bromodomain , acetamide , cocrystal , substituent , selectivity , stereochemistry , potency , brd4 , protonation , medicinal chemistry , in vitro , biochemistry , organic chemistry , molecule , histone , hydrogen bond , gene , catalysis , ion
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‐[(9 S )‐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 n m vs . BRD4(1) and a ca . 2‐fold selectivity over BRD4(2) ( K D = ca . 260 n m ). Its binding to the first bromodomain of BRD4 was determined by a protein cocrystal structure.