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

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• 作者：Akihiko Nishikimi¹ ; ² ; ⁵ ; ¹⁰ ; Takehito Uruno¹ ; ¹⁰ ; Xuefeng Duan² ; Qinhong Cao¹ ; Yuji Okamura⁶ ; Takashi Saitoh³ ; Nae Saito⁷ ; Shunsuke Sakaoka⁶ ; Yao Du⁶ ; Atsushi Suenaga⁹ ; Mutsuko Kukimoto-Niino⁵ ; ⁹ ; Kei Miyano⁴ ; Kazuhito Gotoh¹ ; ⁵ ; Takayoshi Okabe⁷ ; Fumiyuki Sanematsu¹ ; ² ; ⁵ ; Yoshihiko Tanaka¹ ; ² ; ⁵ ; Hideki Sumimoto⁴ ; Teruki Honma⁹ ; Shigeyuki Yokoyama⁵ ; ⁸ ; ⁹ ; Tetsuo Nagano⁶ ; ⁷ ; Daisuke Kohda² ; ³ ; Motomu Kanai⁶ ; Yoshinori Fukui¹ ; ² ; ⁵ ; ^{fukui@bioreg.kyushu-u.ac.jp}
• 刊名：Chemistry & Biology
• 出版年：2012
• 出版时间：20 April, 2012
• 年：2012
• 卷：19
• 期：4
• 页码：488-497
• 全文大小：1153 K

文摘

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Summary

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.