SCH 527123 is a potent, selective antagonist of the CXCR1 and CXCR2 receptors with high affinity to the CXCR2 receptors of mouse (Kd=0.20nM), rat (Kd=0.20nM), and cynomolgus monkey (Kd=0.08nM) [1]. SCH 527123 can inhibit tumor growth, microvessel density and CXCR2-mediated signal transduction by reducing the phosphorylation levels of the NF-κB/MAPK/AKT pathway[2]. SCH 527123 has been widely used to inhibit the growth, angiogenesis and metastasis of malignant melanoma[3].
In vitro, SCH 527123 treatment for 72h significantly inhibited the proliferation of Caco2 cells and HCT116 cells, with IC50 values of 18.78μM and 28.95μM, respectively[4]. 80μM of SCH 527123 pretreatment for 4 hours significantly inhibited the proliferation of AsPC-1 cells stimulated by 25ng/ml of IL-8[5].
In vivo, SCH 527123 treatment via oral administration at a dose of 100mg/kg/day for 21 consecutive days inhibits tumor growth in a A375SM cell-xenograft mouse model and reduce the density of tumor microvessels[6]. Oral administration of SCH 527123 (3mg/kg) 2 hours before and 4 hours after lipopolysaccharide challenge suppresses pulmonary neutrophilia and goblet cell hyperplasia in mice[7]. Twice-daily oral administration of SCH 527123 at a dose of 10mg/kg for 21 consecutive days inhibited leukocyte migration into the lungs and reversed pulmonary arterial hypertension in L1Cre(+);Bmpr2f/f mice[8].
References:
[1] Chapman R W, Minnicozzi M, Celly C S, et al. A novel, orally active CXCR1/2 receptor antagonist, Sch527123, inhibits neutrophil recruitment, mucus production, and goblet cell hyperplasia in animal models of pulmonary inflammation[J]. The Journal of pharmacology and experimental therapeutics, 2007, 322(2): 486-493.
[2] Xu X, Xia J, Wang X. Potential anticancer therapies via CXCL5 and its receptors[J]. Expert Review of Clinical Pharmacology, 2012, 5(4): 347-350.
[3] Sharma B, Singh S, Varney M L, et al. Targeting CXCR1/CXCR2 receptor antagonism in malignant melanoma[J]. Expert opinion on therapeutic targets, 2010, 14(4): 435-442.
[4] Ning Y, Labonte M J, Zhang W, et al. The CXCR2 antagonist, SCH-527123, shows antitumor activity and sensitizes cells to oxaliplatin in preclinical colon cancer models[J]. Molecular cancer therapeutics, 2012, 11(6): 1353-1364.
[5] Fu S, Chen X, Lin H J, et al. Inhibition of interleukin 8/C‑XC chemokine receptor 1,/2 signaling reduces malignant features in human pancreatic cancer cells[J]. International Journal of Oncology, 2018, 53(1): 349-357.
[6] Singh S, Sadanandam A, Nannuru K C, et al. Small-molecule antagonists for CXCR2 and CXCR1 inhibit human melanoma growth by decreasing tumor cell proliferation, survival, and angiogenesis[J]. Clinical Cancer Research, 2009, 15(7): 2380-2386.
[7] Chapman R W, Minnicozzi M, Celly C S, et al. A novel, orally active CXCR1/2 receptor antagonist, Sch527123, inhibits neutrophil recruitment, mucus production, and goblet cell hyperplasia in animal models of pulmonary inflammation[J]. The Journal of pharmacology and experimental therapeutics, 2007, 322(2): 486-493.
[8] Burton V J, Holmes A M, Ciuclan L I, et al. Attenuation of leukocyte recruitment via CXCR1/2 inhibition stops the progression of PAH in mice with genetic ablation of endothelial BMPR-II[J]. Blood, The Journal of the American Society of Hematology, 2011, 118(17): 4750-4758.
SCH 527123是一种强效、选择性的CXCR1和CXCR2受体拮抗剂，对小鼠（Kd=0.20nM）、大鼠（Kd=0.20nM）和食蟹猴（Kd=0.08nM）的CXCR2受体具有高亲和力[1]。SCH 527123可通过降低NF-κB/MAPK/AKT通路的磷酸化水平，抑制肿瘤生长、微血管密度和CXCR2介导的信号转导[2]。SCH 527123已广泛应用于抑制恶性黑色素瘤的生长、血管生成和转移[3]。
在体外，SCH 527123处理72小时显著抑制了Caco2细胞和HCT116细胞的增殖，IC50值分别为18.78μM 和28.95μM[4]。用80μM的SCH 527123预处理4小时显著抑制了由25ng/ml的IL-8刺激AsPC-1细胞增殖[5]。
在体内，以100mg/kg/day的剂量连续21天口服SCH 527123，可抑制A375SM细胞异种移植小鼠模型的肿瘤生长并降低肿瘤微血管密度[6]。在脂多糖刺激前2小时和刺激后4小时分别口服SCH 527123（3mg/kg）可抑制小鼠肺部中性粒细胞增多和杯状细胞增生[7]。每日两次口服10mg/kg剂量的SCH 527123，连续21天，可抑制白细胞向肺部迁移，并逆转L1Cre(+);Bmpr2f/f小鼠的肺动脉高压[8]。