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
  • 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: [email protected].
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.