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  3. 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

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

  • Bioorg Med Chem Lett. 2016 Mar 1;26(5):1365-70. doi: 10.1016/j.bmcl.2016.01.084.
Junichi Endo 1,  Hidemasa Hikawa 1,  Maiko Hamada 1,  Seigo Ishibuchi 1,  Naoto Fujie 1,  Naoki Sugiyama 1,  Minoru Tanaka 1,  Haruhito Kobayashi 1,  Kunio Sugahara 1,  Koichi Oshita 1,  Kazunori Iwata 1,  Shinsuke Ooike 1,  Meguru Murata 1,  Hiroshi Sumichika 1,  Kenji Chiba 1,  Kunitomo Adachi 2
Affiliations

Affiliations

  • 1 Research Unit B, Research Division, Mitsubishi Tanabe Pharma Corporation, 1000, Kamoshida-cho, Aoba-ku, Yokohama, Kanagawa 227-0033, Japan.
  • 2 Research Unit B, Research Division, Mitsubishi Tanabe Pharma Corporation, 1000, Kamoshida-cho, Aoba-ku, Yokohama, Kanagawa 227-0033, Japan. Electronic address: Adachi.Kunitomo@mc.mt-pharma.co.jp.
PMID: 26869194 DOI: 10.1016/j.bmcl.2016.01.084
Abstract

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.

Keywords

Anti-cancer; BET family; Bromodomain; CD28; Chemical biology; Immunosuppressant; Phenotypic drug discovery.

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