TY - JOUR
T1 - Blockade of inflammatory responses by a small-molecule inhibitor of the Rac activator DOCK2
AU - Nishikimi, Akihiko
AU - Uruno, Takehito
AU - Duan, Xuefeng
AU - Cao, Qinhong
AU - Okamura, Yuji
AU - Saitoh, Takashi
AU - Saito, Nae
AU - Sakaoka, Shunsuke
AU - Du, Yao
AU - Suenaga, Atsushi
AU - Kukimoto-Niino, Mutsuko
AU - Miyano, Kei
AU - Gotoh, Kazuhito
AU - Okabe, Takayoshi
AU - Sanematsu, Fumiyuki
AU - Tanaka, Yoshihiko
AU - Sumimoto, Hideki
AU - Honma, Teruki
AU - Yokoyama, Shigeyuki
AU - Nagano, Tetsuo
AU - Kohda, Daisuke
AU - Kanai, Motomu
AU - Fukui, Yoshinori
N1 - Funding Information:
We thank A. Inayoshi and M. Sanematsu for technical assistance. This work was supported by grants for Targeted Proteins Research Program from the Ministry of Education, Culture, Sports, Science and Technology of Japan, Grants-in-Aid for Scientific Research from the Japan Society for the promotion of Science, CREST program of Japan Science and Technology Agency, the Kanae Foundation, the Mochida Memorial Foundation, and the Tokyo Biochemical Research Foundation.
PY - 2012/4/20
Y1 - 2012/4/20
N2 - 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.
AB - 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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U2 - 10.1016/j.chembiol.2012.03.008
DO - 10.1016/j.chembiol.2012.03.008
M3 - Article
C2 - 22520755
AN - SCOPUS:84860110971
SN - 2451-9448
VL - 19
SP - 488
EP - 497
JO - Cell Chemical Biology
JF - Cell Chemical Biology
IS - 4
ER -