CPYPP bound to DOCK2 DHR-2 domain (DOCK2DHR-2) in a reversible manner and inhibited its catalytic activity[1].
CPYPP inhibited the guanine nucleotide exchange factor (GEF) activity of DOCK2DHR-2 for Rac1 in a dose-dependent manner, with a half-maximal inhibitory concentration (IC50) of 22.8 ± 2.4 μM. This inhibitory activity was independent on length of preincubation time, ranging from 2 min to 30 min. In addition, CPYPP was nontoxic when applied to spleen cells or thymoma cells (BW5147α-β-) at 100 μM for 3 hr or 3 days, respectively [1]. Pre-treatment of human neutrophils with CPYPP, a small molecule inhibitor of the DHR-2 domain of DOCK proteins and thus of the Rac GEF activity of human DOCK2 and DOCK5, significantly impaired neutrophil chemotaxis and ROS production [2].
CPYPP effectively decreased the secretion and gene expression of TNF-α, IL-1β and IL-6 in the lungs, suggested effects of DOCK2 on endotoxemia-induced inflammatory responses in mice. CPYPP remarkably inhibited the infiltration of total cells, macrophages and neutrophils into the bronchoalveolar lavage fluid [3]. A reseach found out that a joint usage of both CPYPP and C25-140 revealed a better consequence compared to monotherapy against hepatic I/R injury [4].
References:
[1]. Nishikimi?A, Uruno?T, Duan?X, Cao?Q, Okamura?Y, Saitoh?T, et al.?Blockade of inflammatory responses by a small-molecule inhibitor of the Rac activator DOCK2. Chem Biol?2012;19:488-97.
[2]. Moens, L., Gouwy, M., Bosch, B. et al. 2019. Human DOCK2 deficiency: report of a novel mutation and evidence for neutrophil dysfunction. J. Clin. Immunol. 39:298.
[3]. Xu, X., Su, Y., Wu, K., Pan, F. & Wang, A. DOCK2 contributes to endotoxemia-induced acute lung injury in mice by activating proinflammatory macrophages. Biochem. Pharmacol. 181, 114399 (2021).
[4]. Zuotian Huang, Junliang Pua, Yunhai Luo, et al. FAM49B, restrained by miR-22, relieved hepatic ischemia/reperfusion injury by inhibiting TRAF6/IKK signaling pathway in a Rac1-dependent manner. Molecular Immunology.143, 2022, 135-146.
CPYPP 以可逆方式与 DOCK2 DHR-2 结构域 (DOCK2DHR-2) 结合并抑制其催化活性[1]。
CPYPP 以剂量依赖性方式抑制 DOCK2DHR-2 鸟嘌呤核苷酸交换因子 (GEF) 对 Rac1 的活性，半数最大抑制浓度 (IC50) 为 22.8 ± 2.4 μM .这种抑制活性与预孵育时间的长度无关，范围从 2 分钟到 30 分钟。此外，CPYPP 在以 100 μM 分别作用于脾细胞或胸腺瘤细胞 (BW5147α-β-) 3 小时或 3 天时是无毒的[1]。用 CPYPP 预处理人中性粒细胞，CPYPP 是一种小分子抑制剂，可抑制 DOCK 蛋白的 DHR-2 结构域，从而抑制人 DOCK2 和 DOCK5 的 Rac GEF 活性，显着损害中性粒细胞趋化性和 ROS 产生[2].
CPYPP 有效降低肺部 TNF-α、IL-1β 和 IL-6 的分泌和基因表达，表明 DOCK2 对小鼠内毒素血症诱导的炎症反应有影响。 CPYPP显着抑制总细胞、巨噬细胞和中性粒细胞向支气管肺泡灌洗液中的浸润[3]。一项研究发现，与单一疗法相比，CPYPP 和 C25-140 联合使用对肝 I/R 损伤具有更好的疗效[4]。