2. Academic Validation
  3. Blockade of inflammatory responses by a small-molecule inhibitor of the Rac activator DOCK2

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

  • Chem Biol. 2012 Apr 20;19(4):488-97. doi: 10.1016/j.chembiol.2012.03.008.
Akihiko Nishikimi 1,  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
Affiliations

Affiliation

  • 1 Division of Immunogenetics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan.
PMID: 22520755 DOI: 10.1016/j.chembiol.2012.03.008
Abstract

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.

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