A phenotypic drug discovery study on thienodiazepine derivatives as inhibitors of T cell proliferation induced by CD28 co-stimulation leads to the discovery of a first bromodomain inhibitor

详细信息    查看全文

• 作者：Junichi Endo ; Hidemasa Hikawa ; Maiko Hamada ; Seigo Ishibuchi ; Naoto Fujie ; Naoki Sugiyama ; Minoru Tanaka ; Haruhito Kobayashi ; Kunio Sugahara ; Koichi Oshita ; Kazunori Iwata ; Shinsuke Ooike ; Meguru Murata ; Hiroshi Sumichika ; Kenji Chiba ; Kunitomo Adachi ; ^{Adachi.Kunitomo@mc.mt-pharma.co.jp" class="auth_mail" title="E-mail the corresponding author}
• 关键词：CD28 ; Phenotypic drug discovery ; Chemical biology ; BET family ; Bromodomain ; Immunosuppressant ; Anti-cancer
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：1 March 2016
• 年：2016
• 卷：26
• 期：5
• 页码：1365-1370
• 全文大小：1305 K

文摘

A phenotypic screening of thienodiazepines derived from a hit compound found through a binding assay targeting co-stimulatory molecules on T cells and antigen presenting cells successfully led to the discovery of a thienotriazolodiazepine compound (7f) possessing potent immunosuppressive activity. A chemical biology approach has succeeded in revealing that 7f is a first inhibitor of epigenetic bromodomain-containing proteins. 7f is expected to become an anti-cancer agent as well as an immunosuppressive agent.