title: 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.
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.
authors: Research Unit B, Research Division, Mitsubishi Tanabe Pharma Corporation, 1000, Kamoshida-cho, Aoba-ku, Yokohama, Kanagawa 227-0033, Japan.
authors: Junichi
authors: J
authors: Endo
authors: Research Unit B, Research Division, Mitsubishi Tanabe Pharma Corporation, 1000, Kamoshida-cho, Aoba-ku, Yokohama, Kanagawa 227-0033, Japan.
authors: Hidemasa
authors: H
authors: Hikawa
authors: Research Unit B, Research Division, Mitsubishi Tanabe Pharma Corporation, 1000, Kamoshida-cho, Aoba-ku, Yokohama, Kanagawa 227-0033, Japan.
authors: Maiko
authors: M
authors: Hamada
authors: Research Unit B, Research Division, Mitsubishi Tanabe Pharma Corporation, 1000, Kamoshida-cho, Aoba-ku, Yokohama, Kanagawa 227-0033, Japan.
authors: Seigo
authors: S
authors: Ishibuchi
authors: Research Unit B, Research Division, Mitsubishi Tanabe Pharma Corporation, 1000, Kamoshida-cho, Aoba-ku, Yokohama, Kanagawa 227-0033, Japan.
authors: Naoto
authors: N
authors: Fujie
authors: Research Unit B, Research Division, Mitsubishi Tanabe Pharma Corporation, 1000, Kamoshida-cho, Aoba-ku, Yokohama, Kanagawa 227-0033, Japan.
authors: Naoki
authors: N
authors: Sugiyama
authors: Research Unit B, Research Division, Mitsubishi Tanabe Pharma Corporation, 1000, Kamoshida-cho, Aoba-ku, Yokohama, Kanagawa 227-0033, Japan.
authors: Minoru
authors: M
authors: Tanaka
authors: Research Unit B, Research Division, Mitsubishi Tanabe Pharma Corporation, 1000, Kamoshida-cho, Aoba-ku, Yokohama, Kanagawa 227-0033, Japan.
authors: Haruhito
authors: H
authors: Kobayashi
authors: Research Unit B, Research Division, Mitsubishi Tanabe Pharma Corporation, 1000, Kamoshida-cho, Aoba-ku, Yokohama, Kanagawa 227-0033, Japan.
authors: Kunio
authors: K
authors: Sugahara
authors: Research Unit B, Research Division, Mitsubishi Tanabe Pharma Corporation, 1000, Kamoshida-cho, Aoba-ku, Yokohama, Kanagawa 227-0033, Japan.
authors: Koichi
authors: K
authors: Oshita
authors: Research Unit B, Research Division, Mitsubishi Tanabe Pharma Corporation, 1000, Kamoshida-cho, Aoba-ku, Yokohama, Kanagawa 227-0033, Japan.
authors: Kazunori
authors: K
authors: Iwata
authors: Research Unit B, Research Division, Mitsubishi Tanabe Pharma Corporation, 1000, Kamoshida-cho, Aoba-ku, Yokohama, Kanagawa 227-0033, Japan.
authors: Shinsuke
authors: S
authors: Ooike
authors: Research Unit B, Research Division, Mitsubishi Tanabe Pharma Corporation, 1000, Kamoshida-cho, Aoba-ku, Yokohama, Kanagawa 227-0033, Japan.
authors: Meguru
authors: M
authors: Murata
authors: Research Unit B, Research Division, Mitsubishi Tanabe Pharma Corporation, 1000, Kamoshida-cho, Aoba-ku, Yokohama, Kanagawa 227-0033, Japan.
authors: Hiroshi
authors: H
authors: Sumichika
authors: Research Unit B, Research Division, Mitsubishi Tanabe Pharma Corporation, 1000, Kamoshida-cho, Aoba-ku, Yokohama, Kanagawa 227-0033, Japan.
authors: Kenji
authors: K
authors: Chiba
authors: 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.
authors: Kunitomo
authors: K
authors: Adachi
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001381:Azepines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018106:CD28 Antigens / Q000276:immunology / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004354:Drug Screening Assays, Antitumor; D051548:Histone Acetyltransferases; D056488:Histone Chaperones; D006801:Humans; D007166:Immunosuppressive Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D010641:Phenotype; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000166:cytology* / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D000092468:Bromodomain Containing Proteins
chemical_list: D000970:Antineoplastic Agents; D001381:Azepines; D018106:CD28 Antigens; D051548:Histone Acetyltransferases; D056488:Histone Chaperones; D007166:Immunosuppressive Agents; D009687:Nuclear Proteins; C013295:thienodiazepine substance; C402649:BRD1 protein, human; D000092468:Bromodomain Containing Proteins
keywords: Anti-cancer; BET family; Bromodomain; CD28; Chemical biology; Immunosuppressant; Phenotypic drug discovery