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

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.

Automated summary

A series of bulky organometallic and organic analogues of the bromodomain (BRD) inhibitor (+)-JQ1 have been synthesized, with the most potent compound showing excellent potency and selectivity towards BRD4(1) and BRD4(2). The binding of this compound to the first bromodomain of BRD4 was determined by a protein cocrystal structure.