論文

査読有り
2012年4月

Blockade of Inflammatory Responses by a Small-Molecule Inhibitor of the Rac Activator DOCK2

CHEMISTRY & BIOLOGY
  • Akihiko Nishikimi
  • ,
  • Takehito Uruno
  • ,
  • Xuefeng Duan
  • ,
  • Qinhong Cao
  • ,
  • Yuji Okamura
  • ,
  • Takashi Saitoh
  • ,
  • Nae Saito
  • ,
  • Shunsuke Sakaoka
  • ,
  • Yao Du
  • ,
  • Atsushi Suenaga
  • ,
  • Mutsuko Kukimoto-Niino
  • ,
  • Kei Miyano
  • ,
  • Kazuhito Gotoh
  • ,
  • Takayoshi Okabe
  • ,
  • Fumiyuki Sanematsu
  • ,
  • Yoshihiko Tanaka
  • ,
  • Hideki Sumimoto
  • ,
  • Teruki Honma
  • ,
  • Shigeyuki Yokoyama
  • ,
  • Tetsuo Nagano
  • ,
  • Daisuke Kohda
  • ,
  • Motomu Kanai
  • ,
  • Yoshinori Fukui

19
4
開始ページ
488
終了ページ
497
記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.1016/j.chembiol.2012.03.008
出版者・発行元
CELL PRESS

Tissue infiltration of activated lymphocytes is a hallmark of transplant rejection and organ-specific autoimmune diseases. Migration and activation of lymphocytes depend on DOCK2, an atypical Rac activator predominantly expressed in hematopoietic cells. Although DOCK2 does not contain Dbl homology domain typically found in guanine nucleotide exchange factors, DOCK2 mediates the GTP-GDP exchange reaction for Rac through its DHR-2 domain. Here, we have identified 4-[3'-(2 ''-chlorophenyl)-2'-propen-1'-ylidene]-1-phenyl-3,5-pyrazolidinedione (CPYPP) as a small-molecule inhibitor of DOCK2. CPYPP bound to DOCK2 DHR-2 domain in a reversible manner and inhibited its catalytic activity in vitro. When lymphocytes were treated with CPYPP, both chemokine receptor- and antigen receptor-mediated Rac activation were blocked, resulting in marked reduction of chemotactic response and T cell activation. These results provide a rational of and a chemical scaffold for development of the DOCK2-targeting immunosuppressant.

Web of Science ® 被引用回数 : 43

リンク情報
DOI
https://doi.org/10.1016/j.chembiol.2012.03.008
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/22520755
Web of Science
https://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=JSTA_CEL&SrcApp=J_Gate_JST&DestLinkType=FullRecord&KeyUT=WOS:000303371500011&DestApp=WOS_CPL

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