Chemistry & Biology
Volume 19, Issue 4, 20 April 2012, Pages 488-497
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Article
Blockade of Inflammatory Responses by a Small-Molecule Inhibitor of the Rac Activator DOCK2

https://doi.org/10.1016/j.chembiol.2012.03.008Get rights and content
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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.

Highlights

► CPYPP binds to DOCK2 DHR-2 domain and inhibits its catalytic activity ► CPYPP inhibits DOCK2-mediated Rac activation in cells ► The structural features of CPYPP required for its inhibitory effect were revealed ► CPYPP inhibits lymphocyte migration and activation in vitro and in vivo

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These authors contributed equally to this work