Probing BRD Inhibition Substituent Effects in Bulky Analogues of (+)‐JQ1

• Published in: Helvetica chimica acta Vol. 104; no. 3
• Main Authors: 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, Spencer, John
• Format: Journal Article
• Language: English
• Published: Zürich Wiley Subscription Services, Inc 01-03-2021; Wiley
• Subjects: benzodiazepines; bioinorganic chemistry; bioorganometallic chemistry; bromodomain; cancer; Chemical Sciences; epigenetics; Medicinal Chemistry; Protein structure; Selectivity; Bioorganic chemistry; Benzodiazepine; Cancer
• ISSN: 0018-019X; 1522-2675
• DOI: 10.1002/hlca.202000214

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.