Journal
CHEMISTRY & BIOLOGY
Volume 19, Issue 4, Pages 488-497Publisher
CELL PRESS
DOI: 10.1016/j.chembiol.2012.03.008
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Funding
- Ministry of Education, Culture, Sports, Science and Technology of Japan
- Japan Society for the promotion of Science
- CREST of Japan Science and Technology Agency
- Kanae Foundation
- Mochida Memorial Foundation
- Tokyo Biochemical Research Foundation
- Grants-in-Aid for Scientific Research [22247017, 24111001, 24590586, 23790338] Funding Source: KAKEN
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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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