Nexinhib20 is an inhibitor of neutrophil exocytosis, with an IC50 value of 2.6μM for targeting Rab27a-JFC1 binding [1]. Nexinhib20 limits β2 integrin mobilization and availability at the cell surface while indirectly affecting active integrin avidity [2]. Nexinhib20 has been widely used to inhibit neutrophil adhesion and β2 integrin activation[3].
In vitro, Nexinhib20 treatment for 48 hours significantly inhibited the viability of N417 cells, H524 cells, and N417 H889 cells, with IC50 values of 12.91μM, 1.55μM and 8.58μM, respectively[4]. Treatment with 5μM Nexinhib20 for 48 hours enhanced the immunosuppressive function of eosinophils derived from patients with allergic rhinitis (AR)[5]. Treatment with 10μM Nexinhib20 for 15 minutes reversed the increase in FcgRI in neutrophils stimulated by heat-aggregated IgG and inhibited the production of ROS[6].
In vivo, Nexinhib20 treatment via intraperitoneal injection at a dose of 20mg/kg, twice a week for 4 weeks, significantly inhibited tumor growth in a mouse xenograft model derived from pancreatic ductal adenocarcinom[7]. Intraperitoneal injection of a single dose of Nexinhib20 (100mM in 10μl DMSO) 30 minutes before reperfusion inhibited the recruitment of neutrophils and significantly reduced the infarct area in mice after myocardial ischemia/reperfusion injury[8].
References:
[1] Johnson J L, Ramadass M, He J, et al. Identification of neutrophil exocytosis inhibitors (Nexinhibs), small molecule inhibitors of neutrophil exocytosis and inflammation: druggability of the small GTPase Rab27a[J]. Journal of Biological Chemistry, 2016, 291(50): 25965-25982.
[2] Askari K, Johnson J L, Shukla A, et al. Nexinhib20 inhibits JFC1-mediated mobilization of a subset of CD11b/CD18+ vesicles decreasing integrin avidity, but does not inhibit Rac1[J]. Journal of Leukocyte Biology, 2025, 117(4): qiaf012.
[3] Fan Z, Liu W, Cronin C G, et al. Nexinhib20 prevents myocardial ischemia‐reperfusion injury by inhibiting neutrophil adhesion and β2 integrin activation[J]. The FASEB Journal, 2022, 36.
[4] Irep N, Inci K, Tokgun P E, et al. Exosome inhibition improves response to first‐line therapy in small cell lung cancer[J]. Journal of Cellular and Molecular Medicine, 2024, 28(4): e18138.
[5] Liao Y, Li M, Song S, et al. The Immunosuppressive Functions of Eosinophils Are Compromised in Patients With Allergic Rhinitis, Particularly Concerning Rab27a Expression[J]. Immunity, Inflammation and Disease, 2024, 12(12): e70091.
[6] Huot S, Laflamme C, Fortin P R, et al. IgG‐aggregates rapidly upregulate FcgRI expression at the surface of human neutrophils in a FcgRII‐dependent fashion: a crucial role for FcgRI in the generation of reactive oxygen species[J]. The FASEB Journal, 2020, 34(11): 15208-15221.
[7] Ruivo C F, Bastos N, Adem B, et al. Extracellular vesicles from pancreatic cancer stem cells lead an intratumor communication network (EVNet) to fuel tumour progression[J]. Gut, 2022, 71(10): 2043-2068.
[8] Liu W, Cronin C G, Cao Z, et al. Nexinhib20 Inhibits Neutrophil Adhesion and β2 Integrin Activation by Antagonizing Rac-1–Guanosine 5′-Triphosphate Interaction[J]. The Journal of Immunology, 2022, 209(8): 1574-1585.
Nexinhib20是一种中性粒细胞胞吐抑制剂，靶向Rab27a-JFC1结合的IC50值为2.6µM [1]。Nexinhib20限制β2整合素在细胞表面的动员和可用性，同时间接影响活性整合素的亲和力[2]。Nexinhib20已被广泛用于抑制中性粒细胞粘附和β2整合素激活[3]。
在体外，Nexinhib20处理48小时显著抑制了N417细胞、H524细胞和N417 H889细胞的活力，IC50值分别为12.91µM、1.55µM和8.58µM[4]。使用5µM的Nexinhib20处理48小时，增强了来自过敏性鼻炎（AR）患者嗜酸性粒细胞的免疫抑制功能[5]。使用10µM的Nexinhib20处理15分钟，逆转了热聚集IgG刺激的中性粒细胞中FcgRI的增加，并抑制了ROS的产生[6]。
在体内，每周两次腹腔注射20mg/kg剂量的Nexinhib20，持续4周，显著抑制了胰腺导管腺癌来源的小鼠异种移植模型中的肿瘤生长[7]。在再灌注前30分钟给小鼠单次腹腔注射Nexinhib20（100mM；溶于10µl DMSO），抑制了中性粒细胞的募集，并显著减少了心肌缺血/再灌注损伤后的梗死面积[8]。