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
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DOI：
10.1016/j.chembiol.2012.03.008
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发表时间：
2012-04-20
影响因子：
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通讯作者：
Fukui, Yoshinori
中科院分区：
文献类型：
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作者：
Nishikimi, Akihiko;Uruno, Takehito;Fukui, Yoshinori
活化淋巴细胞的组织浸润是移植排斥和器官特异性自身免疫性疾病的标志。淋巴细胞的迁移和活化依赖于DOCK 2，一种主要在造血细胞中表达的非典型Rac活化剂。虽然DOCK 2不包含通常在鸟嘌呤核苷酸交换因子中发现的Db 1同源结构域，但DOCK 2通过其DHR-2结构域介导Rac的GTP-GDP交换反应。在这里，我们已经确定了4-[3 '-（2“-氯苯基）-2'-亚丙烯-1 '-基]-1-苯基-3，5-吡唑烷二酮（CPYPP）作为DOCK 2的小分子抑制剂。CPYPP与DOCK 2的DHR-2结构域可逆结合，并抑制其体外催化活性。当用CPYPP处理淋巴细胞时，趋化因子受体和抗原受体介导的Rac活化都被阻断，导致趋化反应和T细胞活化显著降低。这些结果为DOCK 2靶向免疫抑制剂的开发提供了理论依据和化学支架。
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.