SX-682 is an orally bioavailable small-molecule inhibitor of CXCR1 and CXCR2 with IC50 values of 31 and 21nM, respectively [1]. SX-682 effective at promoting a switch from a mesenchymal to an epithelial tumor phenotype, while simultaneously enhancing the tumor cells’ susceptibility to immune-mediated cytotoxicity [2]. SX-682 has been widely used as an anti-cancer agent to inhibit the progression of colorectal cancer[3].
In vitro, SX-682 (5μM) treatment for 4 days significantly inhibited the growth of B16F0 and B16F10 cells, and reduced the production of Cxcl1 and vascular endothelial growth factor (VEGF)[4]. The combined treatment of 2.5µM SX-682 and 25µg/mL bintrafusp alfa for 3 days led to a significant aggregation of 4T1 cells, upregulated the expression of E-cadherin, and decreased the expressions of mesenchymal cell vimentin, as well as mesenchymal transcription factors Snail and Zeb-1[5]. 10µM SX-682 pretreatment for 72 hours significantly enhanced the sensitivity of UM-SCC-11B cells to docetaxel, and greatly reduced cell viability[6].
In vivo, SX-682 treatment via oral administration at a dose of 200mg/kg dose twice daily for 2 weeks significantly inhibited the growth of lung tumors in mice, without reducing the content of tumor-associated neutrophils[7]. The combined treatment with SX-682 (0.756g/kg/day; p.o.) and anti-PD-1 antibody for 3 weeks significantly inhibited the growth of tumors in Rich1.1 melanoma cell-xenograft mouse model, reduced the myeloid-derived suppressor cells (MDSC) within the tumors, and increased the B1b cells expressing CXCL11 within the tumors[8].
References:
[1] Maeda D Y, Peck A M, Schuler A D, et al. Boronic acid-containing CXCR1/2 antagonists: Optimization of metabolic stability, in vivo evaluation, and a proposed receptor binding model[J]. Bioorganic & medicinal chemistry letters, 2015, 25(11): 2280-2284.
[2] Horn L, Hamilton D, Maeda D, et al. Abstract B04: Multimodal cancer immunotherapy combining IL-8 inhibition, adenovirus vaccine, IL-15 super agonist, and anti-PD-L1/TGFβRII agent reduces mesenchymalization and enhances anti-tumor efficacy[J]. Cancer Immunology Research, 2020, 8(4_Supplement): B04-B04.
[3] Sherry C, Dadgar N, Liu Z, et al. The Interleukin-8-CXCR1/2 Axis as a Therapeutic Target in Peritoneal Carcinomatosis[J]. Current Oncology, 2025, 32(9): 496.
[4] Yang J, Bergdorf K, Yan C, et al. CXCR2 expression during melanoma tumorigenesis controls transcriptional programs that facilitate tumor growth[J]. Molecular Cancer, 2023, 22(1): 92.
[5] Horn L A, Riskin J, Hempel H A, et al. Simultaneous inhibition of CXCR1/2, TGF-β, and PD-L1 remodels the tumor and its microenvironment to drive antitumor immunity[J]. Journal for immunotherapy of cancer, 2020, 8(1): e000326.
[6] Horn L A, Lind H, Fousek K, et al. Inhibition of the chemokine receptors CXCR1 and CXCR2 synergizes with docetaxel for effective tumor control and remodeling of the immune microenvironment of HPV-negative head and neck cancer models[J]. Journal of Experimental & Clinical Cancer Research, 2024, 43(1): 318
[7] Kwak J W, Nguyen H Q, Camai A, et al. CXCR1/2 antagonism inhibits neutrophil function and not recruitment in cancer[J]. Oncoimmunology, 2024, 13(1): 2384674.
[8] Yang J, Yan C, Vilgelm A E, et al. Targeted deletion of CXCR2 in myeloid cells alters the tumor immune environment to improve antitumor immunity[J]. Cancer immunology research, 2021, 9(2): 200-213.
SX-682是一种口服生物可利用的小分子CXCR1和CXCR2抑制剂，IC50值分别为31nM和21nM[1]。SX-682能有效促进肿瘤表型从间充质向上皮转化，同时增强肿瘤细胞对免疫介导的细胞毒作用的敏感性[2]。SX-682已广泛用作抗癌剂，以抑制结直肠癌的进展[3]。
在体外，SX-682（5μM）处理4天显著抑制了B16F0和B16F10细胞的生长，并减少了Cxcl1和血管内皮生长因子(VEGF)的产生[4]。2.5µM的SX-682与25µg/ml的bintrafusp alfa联合处理3天导致4T1细胞显著聚集，上调了E-钙粘蛋白的表达，并降低了间充质细胞波形蛋白以及间充质转录因子Snail和Zeb-1的表达[5]。10µM的SX-682预处理72小时显著增强了UM-SCC-11B细胞对docetaxel的敏感性，并显著降低了细胞活力[6]。
在体内，以200mg/kg剂量每日两次口服SX-682连续2周显著抑制了小鼠肺部肿瘤的生长，且未降低肿瘤相关中性粒细胞的含量[7]。SX-682（0.756g/kg/day；口服）与抗PD-1抗体联合治疗3周显著抑制了Rich1.1黑色素瘤细胞异种移植小鼠模型的肿瘤生长，减少了肿瘤内的髓源性抑制细胞(MDSC)，并增加了肿瘤内表达CXCL11的B1b细胞[8]。