Blockade of inflammatory responses by a small-molecule inhibitor of the Rac activator DOCK2

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 NaganoDaisuke Kohda, Motomu Kanai, Yoshinori Fukui

研究成果: ジャーナルへの寄稿学術誌査読

58 被引用数 (Scopus)

抄録

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.

本文言語英語
ページ(範囲)488-497
ページ数10
ジャーナルChemistry and Biology
19
4
DOI
出版ステータス出版済み - 4月 20 2012

!!!All Science Journal Classification (ASJC) codes

  • 生化学
  • 分子医療
  • 分子生物学
  • 薬理学
  • 創薬
  • 臨床生化学

フィンガープリント

「Blockade of inflammatory responses by a small-molecule inhibitor of the Rac activator DOCK2」の研究トピックを掘り下げます。これらがまとまってユニークなフィンガープリントを構成します。

引用スタイル