SX-682
目录号 : GC38204
SX-682 is an orally bioavailable small-molecule allosteric inhibitor of CXCR1 and CXCR2 that blocks tumor MDSC recruitment and enhances T cell activation and antitumor immunity.
Cas No.:1648843-04-2
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
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- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
SX-682 is an orally bioavailable small-molecule allosteric inhibitor of CXCR1 and CXCR2 that blocks tumor MDSC recruitment and enhances T cell activation and antitumor immunity.
Whole tumor accumulation of CXCL1 in vivo in MOC1 and LLC tumors is significantly greater than oral mucosa and normal lung, respectively, and not diminished with SX-682 treatment. Plasma accumulation of CXCL1 is greater in tumor-bearing mice compared with naive for both models and increases following SX-682 treatment. Treatment of mice bearing MOC1 or LLC tumors with SX-682 beginning 10 or 20 days after tumor initiation does not alter CXCR1 or CXCR2 expression on tumor cells in vivo.[2] Following in vivo SX-682 treatment, tumor PMN-MDSC expression of cell surface TGF-β or superoxide dismutase 1/2 genes, responsible for the generation of H2O2, is not significantly altered.[3]
[1] Xin Lu, et al. Nature. 2017 Mar 30;543(7647):728-732. [2] Lillian Sun, et al. JCI Insight. 2019 Apr 4;4(7):e126853. [3] Sarah Greene, et al. Clin Cancer Res. 2020 Mar 15;26(6):1420-1431.
| Cas No. | 1648843-04-2 | SDF | |
| Canonical SMILES | O=C(NC1=CC=C(F)C=C1)C(C=N2)=CN=C2SCC3=CC(OC(F)(F)F)=CC=C3B(O)O | ||
| 分子式 | C19H14BF4N3O4S | 分子量 | 467.2 |
| 溶解度 | DMSO: 250 mg/mL (535.10 mM) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.1404 mL | 10.7021 mL | 21.4041 mL |
| 5 mM | 0.4281 mL | 2.1404 mL | 4.2808 mL |
| 10 mM | 0.214 mL | 1.0702 mL | 2.1404 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Inhibition of MDSC Trafficking with SX-682, a CXCR1/2 Inhibitor, Enhances NK-Cell Immunotherapy in Head and Neck Cancer Models
Clin Cancer Res 2020 Mar 15;26(6):1420-1431.PMID:31848188DOI:10.1158/1078-0432.CCR-19-2625.
Purpose: Natural killer (NK)-cell-based immunotherapy may overcome obstacles to effective T-cell-based immunotherapy such as the presence of genomic alterations in IFN response genes and antigen presentation machinery. All immunotherapy approaches may be abrogated by the presence of an immunosuppressive tumor microenvironment present in many solid tumor types, including head and neck squamous cell carcinoma (HNSCC). Here, we studied the role of myeloid-derived suppressor cells (MDSC) in suppressing NK-cell function in HNSCC. Experimental design: The ability of peripheral and tumor-infiltrating MDSC from mice bearing murine oral cancer 2 (MOC2) non-T-cell-inflamed tumors and from patients with HNSCC to suppress NK-cell function was studied with real-time impedance and ELISpot assays. The therapeutic efficacy of SX-682, a small-molecule inhibitor of CXCR1 and CXCR2, was assessed in combination with adoptively transferred NK cells. Results: Mice bearing MOC2 tumors pathologically accumulate peripheral CXCR2+ neutrophilic-MDSC (PMN-MDSC) that traffic into tumors and suppress NK-cell function through TGFβ and production of H2O2. Inhibition of MDSC trafficking with orally bioavailable SX-682 significantly abrogated tumor MDSC accumulation and enhanced the tumor infiltration, activation, and therapeutic efficacy of adoptively transferred murine NK cells. Patients with HNSCC harbor significant levels of circulating and tumor-infiltrating CXCR1/2+ CD15+ PMN-MDSC and CD14+ monocytic-MDSC. Tumor MDSC exhibited greater immunosuppression than those in circulation. HNSCC tumor MDSC immunosuppression was mediated by multiple, independent, cell-specific mechanisms including TGFβ and nitric oxide. Conclusions: The clinical study of CXCR1/2 inhibitors in combination with adoptively transferred NK cells is warranted.
Inhibiting myeloid-derived suppressor cell trafficking enhances T cell immunotherapy
JCI Insight 2019 Apr 4;4(7):e126853.PMID:30944253DOI:10.1172/jci.insight.126853.
Recruitment of myeloid-derived suppressor cells (MDSCs) into tumors induces local immunosuppression in carcinomas. Here, we assessed whether SX-682, an orally bioavailable small-molecule inhibitor of CXCR1 and CXCR2, could block tumor MDSC recruitment and enhance T cell activation and antitumor immunity following multiple forms of immunotherapy. CXCR2+ neutrophilic MDSCs (PMN-MDSCs) were the most abundant myeloid cell subset within oral and lung syngeneic carcinomas. PMN-MDSCs demonstrated greater suppression of tumor-infiltrating lymphocyte killing of targets compared with macrophages. SX-682 significantly inhibited trafficking of PMN-MDSCs without altering CXCR2 ligand expression. Trafficking of CXCR1+ macrophages was unaltered, possibly due to coexpression of CSF1R. Reduced PMN-MDSC tumor infiltration correlated with enhanced accumulation of endogenous or adoptively transferred T cells. Accordingly, tumor growth inhibition or the rate of established tumor rejection following programed death-axis (PD-axis) immune checkpoint blockade or adoptive cell transfer of engineered T cells was enhanced in combination with SX-682. Despite CXCR1/2 expression on tumor cells, SX-682 appeared to have little direct antitumor effect on these carcinoma models. These data suggest that tumor-infiltrating CXCR2+ PMN-MDSCs may prevent optimal responses following both PD-axis immune checkpoint blockade and adoptive T cell transfer therapy. Abrogation of PMN-MDSC trafficking with SX-682 enhances T cell-based immunotherapeutic efficacy and may be of benefit to patients with MDSC-infiltrated cancers.
CXCR2 expression during melanoma tumorigenesis controls transcriptional programs that facilitate tumor growth
bioRxiv 2023 Mar 4;2023.02.22.529548.PMID:36865260DOI:10.1101/2023.02.22.529548.
Background: Though the CXCR2 chemokine receptor is known to play a key role in cancer growth and response to therapy, a direct link between expression of CXCR2 in tumor progenitor cells during induction of tumorigenesis has not been established. Methods: To characterize the role of CXCR2 during melanoma tumorigenesis, we generated tamoxifen-inducible tyrosinase-promoter driven Braf V600E /Pten -/- /Cxcr2 -/- and NRas Q61R /INK4a -/- /Cxcr2 -/- melanoma models. In addition, the effects of a CXCR1/CXCR2 antagonist, SX-682, on melanoma tumorigenesis were evaluated in Braf V600E /Pten -/- and NRas Q61R /INK4a -/- mice and in melanoma cell lines. Potential mechanisms by which Cxcr2 affects melanoma tumorigenesis in these murine models were explored using RNAseq, mMCP-counter, ChIPseq, and qRT-PCR; flow cytometry, and reverse phosphoprotein analysis (RPPA). Results: Genetic loss of Cxcr2 or pharmacological inhibition of CXCR1/CXCR2 during melanoma tumor induction resulted in key changes in gene expression that reduced tumor incidence/growth and increased anti-tumor immunity. Interestingly, after Cxcr2 ablation, Tfcp2l1 , a key tumor suppressive transcription factor, was the only gene significantly induced with a log 2 fold-change greater than 2 in these three different melanoma models. Conclusions: Here, we provide novel mechanistic insight revealing how loss of Cxcr2 expression/activity in melanoma tumor progenitor cells results in reduced tumor burden and creation of an anti-tumor immune microenvironment. This mechanism entails an increase in expression of the tumor suppressive transcription factor, Tfcp2l1, along with alteration in the expression of genes involved in growth regulation, tumor suppression, stemness, differentiation, and immune modulation. These gene expression changes are coincident with reduction in the activation of key growth regulatory pathways, including AKT and mTOR.
Neutrophil content predicts lymphocyte depletion and anti-PD1 treatment failure in NSCLC
JCI Insight 2019 Dec 19;4(24):e130850.PMID:31852845DOI:10.1172/jci.insight.130850.
Immune checkpoint inhibitor (ICI) treatment has recently become a first-line therapy for many non-small cell lung cancer (NSCLC) patients. Unfortunately, most NSCLC patients are refractory to ICI monotherapy, and initial attempts to address this issue with secondary therapeutics have proven unsuccessful. To identify entities precluding CD8+ T cell accumulation in this process, we performed unbiased analyses on flow cytometry, gene expression, and multiplexed immunohistochemical data from a NSCLC patient cohort. The results revealed the presence of a myeloid-rich subgroup, which was devoid of CD4+ and CD8+ T cells. Of all myeloid cell types assessed, neutrophils were the most highly associated with the myeloid phenotype. Additionally, the ratio of CD8+ T cells to neutrophils (CD8/PMN) within the tumor mass optimally distinguished between active and myeloid cases. This ratio was also capable of showing the separation of patients responsive to ICI therapy from those with stable or progressive disease in 2 independent cohorts. Tumor-bearing mice treated with a combination of anti-PD1 and SX-682 (CXCR1/2 inhibitor) displayed relocation of lymphocytes from the tumor periphery into a malignant tumor, which was associated with induction of IFN-γ-responsive genes. These results suggest that neutrophil antagonism may represent a viable secondary therapeutic strategy to enhance ICI treatment outcomes.
Targeted Deletion of CXCR2 in Myeloid Cells Alters the Tumor Immune Environment to Improve Antitumor Immunity
Cancer Immunol Res 2021 Feb;9(2):200-213.PMID:33177110DOI:10.1158/2326-6066.CIR-20-0312.
Recruitment of myeloid-derived suppressor cells (MDSC) into the tumor microenvironment (TME) contributes to cancer immune evasion. MDSCs express the chemokine receptor CXCR2, and inhibiting CXCR2 suppresses the recruitment of MDSCs into the tumor and the premetastatic niche. Here, we compared the growth and metastasis of melanoma and breast cancer xenografts in mice exhibiting or not exhibiting targeted deletion of Cxcr2 in myeloid cells (CXCR2myeΔ/Δ vs. CXCR2myeWT). Detailed analysis of leukocyte populations in peripheral blood and in tumors from CXCR2myeΔ/Δ mice revealed that loss of CXCR2 signaling in myeloid cells resulted in reduced intratumoral MDSCs and increased intratumoral CXCL11. The increase in intratumoral CXCL11 was derived in part from tumor-infiltrating B1b cells. The reduction in intratumoral MDSCs coupled with an increase in intratumoral B1b cells expressing CXCL11 resulted in enhanced infiltration and activation of effector CD8+ T cells in the TME of CXCR2myeΔ/Δ mice, accompanied by inhibition of tumor growth in CXCR2myeΔ/Δ mice compared with CXCR2myeWT littermates. Treatment of tumor-bearing mice with a CXCR2 antagonist (SX-682) also inhibited tumor growth, reduced intratumoral MDSCs, and increased intratumoral B1b cells expressing CXCL11, leading to an increase in activated CD8+ T cells in the tumor. Depletion of B220+ cells or depletion of CD8+ T cells reversed the tumor-inhibitory properties in CXCR2myeΔ/Δ mice. These data revealed a mechanism by which loss of CXCR2 signaling in myeloid cells modulates antitumor immunity through decreasing MDSCs and enriching CXCL11-producing B1b cells in the TME, which in turn increases CD8+ T-cell recruitment and activation in tumors.