A novel water-soluble benzothiazole derivative BD926 inhibits human activated T cell proliferation by down-regulating the STAT5 activation.
Immunosuppressants are widely used for treatment of T cell-mediated autoimmune diseases and allogeneic graft rejection. However, because of the toxicity and tolerance of these drugs, novel immunosuppressants are urgently needed. We synthesized a series of novel water-soluble benzothiazole derivatives and found that BD926 [sodium 2-(benzo[d]thiazol-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-olate] had potent immunosuppressive activity. Treatment with BD926 significantly inhibited anti-CD3/anti-CD28 and alloantigen-induced human T cell proliferation as well as IL2-stimulated activated T cell proliferation in a dose-dependent manner in vitro. BD926 had no obvious cytotoxicity against human resting T cells, IL-4 treated activated T cells and fibroblast-like synoviocytes in our experimental conditions. Furthermore, BD926 induced cell cycle arrest at G0/G1 phase and inhibited the cyclin D3 and CDK 6 expression in activated T cells. BD926 inhibited the STAT5, but not Akt and p70S6K, phosphorylation in a dose-dependent manner in the IL-2-treated activated T cells. Interestingly, BD926 inhibited IFN-γ, IL-6 and IL-17, but not IL-2, IL-4 and IL-10, production in activated T cells. Finally, treatment with BD926 reduced delayed-type hypersensitivity in mice in a dose-dependent manner. Collectively, these data suggest that BD926 may be a lead compound for the design and development of new immunosuppressants for the intervention of allograft rejection and autoimmune diseases.
Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, People׳s Republic of China; Department of Immunology, School of Basic Medical Sciences, Chengdu Medical College, Chengdu, Sichuan, People׳s Republic of China; Development and Regeneration Key Laboratory of Sichuan Province, Chengdu Medical College, Chengdu, Sichuan, People׳s Republic of China. Electronic address: scunn519@gmail.com.
Yang
Y
Liu
School of laboratory medicine, Chengdu Medical College, Chengdu, Sichuan, People׳s Republic of China. Electronic address: sculy926@126.com.
Yi
Y
Lai
Cancer center, Chengdu Military General Hospital, Chengdu, Sichuan, People׳s Republic of China. Electronic address: huali99@gmail.com.
Hua
H
Li
Department of Immunology, School of Basic Medical Sciences, Chengdu Medical College, Chengdu, Sichuan, People׳s Republic of China. Electronic address: jinliu19871987@163.com.
Jin
J
Liu
Department of Immunology, School of Basic Medical Sciences, Chengdu Medical College, Chengdu, Sichuan, People׳s Republic of China. Electronic address: luoxingyan2006@163.com.
Xing-Yan
XY
Luo
Department of Immunology, School of Basic Medical Sciences, Chengdu Medical College, Chengdu, Sichuan, People׳s Republic of China. Electronic address: limy876@aliyun.com.
Min-Hui
MH
Li
Department of Immunology, School of Basic Medical Sciences, Chengdu Medical College, Chengdu, Sichuan, People׳s Republic of China. Electronic address: yangtai.bio@gmail.com.
Tai
T
Yang
Department of Immunology, School of Basic Medical Sciences, Chengdu Medical College, Chengdu, Sichuan, People׳s Republic of China. Electronic address: yt-wang@hotmail.com.
Yan-Tang
YT
Wang
Department of Immunology, School of Basic Medical Sciences, Chengdu Medical College, Chengdu, Sichuan, People׳s Republic of China. Electronic address: shuxiayang418@gmail.com.
Shu-Xia
SX
Yang
Department of Immunology, School of Basic Medical Sciences, Chengdu Medical College, Chengdu, Sichuan, People׳s Republic of China. Electronic address: limeiligy@gmail.com.
Li-Mei
LM
Li
Department of Immunology, School of Basic Medical Sciences, Chengdu Medical College, Chengdu, Sichuan, People׳s Republic of China. Electronic address: qiangzou99@gmail.com.
Qiang
Q
Zou
Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, People׳s Republic of China. Electronic address: zhlchen@smu.edu.cn.
Zheng-Liang
ZL
Chen
D000818:Animals; D001562:Benzimidazoles / Q000737:chemistry / Q000494:pharmacology*; D052160:Benzothiazoles / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D056743:Cyclin D3 / Q000378:metabolism; D051361:Cyclin-Dependent Kinase 6 / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D017449:Dermatitis, Allergic Contact / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control; D004139:Dinitrofluorobenzene; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D005260:Female; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D007166:Immunosuppressive Agents / Q000737:chemistry / Q000494:pharmacology*; D007191:Indazoles / Q000737:chemistry / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects*; D008807:Mice, Inbred BALB C; D010766:Phosphorylation; D050799:STAT5 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D012995:Solubility; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D014867:Water / Q000737:chemistry*
C000607543:2-(benzo(d)thiazol-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-oic acid; D001562:Benzimidazoles; D052160:Benzothiazoles; C534696:CCND3 protein, human; D056743:Cyclin D3; D016207:Cytokines; D007166:Immunosuppressive Agents; D007191:Indazoles; D050799:STAT5 Transcription Factor; D014867:Water; D004139:Dinitrofluorobenzene; C495911:CDK6 protein, human; D051361:Cyclin-Dependent Kinase 6
BD926; Cytotoxicity; Immunosuppressive activity; T cell proliferation