更新于：2024-11-01

CXCR5 x CXCR3 x CXCR2 x CXCR1

更新于：2024-11-01

基本信息

关联

项与 CXCR5 x CXCR3 x CXCR2 x CXCR1 相关的药物

PXLR

靶点

CXCR1 x CXCR2 x CXCR3 x CXCR5

作用机制

CXCR1拮抗剂 [+3]

在研机构

Chiome Bioscience, Inc.

原研机构

Chiome Bioscience, Inc.

在研适应症

实体瘤

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 CXCR5 x CXCR3 x CXCR2 x CXCR1 相关的临床结果

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100 项与 CXCR5 x CXCR3 x CXCR2 x CXCR1 相关的转化医学

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0 项与 CXCR5 x CXCR3 x CXCR2 x CXCR1 相关的专利（医药）

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项与 CXCR5 x CXCR3 x CXCR2 x CXCR1 相关的文献（医药）

2023-09-14·Cancers

The Role of CXCR1, CXCR2, CXCR3, CXCR5, and CXCR6 Ligands in Molecular Cancer Processes and Clinical Aspects of Acute Myeloid Leukemia (AML).

Review

作者: Kupnicka, Patrycja ; Korbecki, Jan ; Chlubek, Dariusz ; Bosiacki, Mateusz ; Ziętek, Paweł ; Baranowska-Bosiacka, Irena ; Barczak, Katarzyna

Acute myeloid leukemia (AML) is a type of leukemia known for its unfavorable prognoses, prompting research efforts to discover new therapeutic targets. One area of investigation involves examining extracellular factors, particularly CXC chemokines. While CXCL12 (SDF-1) and its receptor CXCR4 have been extensively studied, research on other CXC chemokine axes in AML is less developed. This study aims to bridge that gap by providing an overview of the significance of CXC chemokines other than CXCL12 (CXCR1, CXCR2, CXCR3, CXCR5, and CXCR6 ligands and CXCL14 and CXCL17) in AML's oncogenic processes. We explore the roles of all CXC chemokines other than CXCL12, in particular CXCL1 (Gro-α), CXCL8 (IL-8), CXCL10 (IP-10), and CXCL11 (I-TAC) in AML tumor processes, including their impact on AML cell proliferation, bone marrow angiogenesis, interaction with non-leukemic cells like MSCs and osteoblasts, and their clinical relevance. We delve into how they influence prognosis, association with extramedullary AML, induction of chemoresistance, effects on bone marrow microvessel density, and their connection to French-American-British (FAB) classification and FLT3 gene mutations.

2022-12-01·BMC Pulmonary Medicine

Comprehensive analysis of CXCR family members in lung adenocarcinoma with prognostic values

Article

作者: Hu, Lian-Tao ; Li, Wei-Dong ; Wang, Wei-Qun ; Du, Yun-Ting ; Chu, Zhen-Sheng ; Zhang, Chun-Bin ; Weng, Jin-Ru ; Dong, Xin-Yu ; Deng, Wen-Jun ; Lu, Shi-Zhen ; Ren, Qiao-Sheng ; Li, Xue-Bin ; Li, Yue ; Sun, Luo

AbstractBackgroundThe expression profiles and molecular mechanisms of CXC chemokine receptors (CXCRs) in Lung adenocarcinoma (LUAD) have been extensively explored. However, the comprehensive prognostic values of CXCR members in LUAD have not yet been clearly identified.MethodsMultiple available datasets, including Oncomine datasets, the cancer genome atlas (TCGA), HPA platform, GeneMANIA platform, DAVID platform and the tumor immune estimation resource (TIMER) were used to detect the expression of CXCRs in LUAD, as well as elucidate the significance and value of novel CXCRs-associated genes and signaling pathways in LUAD. ResultsThe mRNA and/or protein expression of CXCR1, CXCR2, CXCR3, CXCR4, CXCR5 and CXCR6 displayed predominantly decreased in LUAD tissues as compared to normal tissues. On the contrary, compared with the normal tissues, the expression of CXCR7 was significantly increased in LUAD tissues. Subsequently, we constructed a network including CXCR family members and their 20 related genes, and the related GO functions assay showed that CXCRs connected with these genes participated in the process of LUAD through several signal pathways including Chemokine signaling pathway, Cytokine-cytokine receptor interaction and Neuroactive ligand-receptor interaction. TCGA and Timer platform revealed that the mRNA expression of CXCR family members was significantly related to individual cancer stages, cancer subtypes, patient’s gender and the immune infiltration level. Finally, survival analysis showed that low mRNA expression levels of CXCR2 (HR = 0.661, and Log-rank P = 1.90e−02), CXCR3 (HR = 0.674, and Log-rank P = 1.00e−02), CXCR4 (HR = 0.65, and Log-rank P = 5.01e−03), CXCR5 (HR = 0.608, and Log-rank P = 4.80e−03) and CXCR6 (HR = 0.622, and Log-rank P = 1.85e−03) were significantly associated with shorter overall survival (OS), whereas high CXCR7 mRNA expression (HR = 1.604, and Log-rank P = 4.27e−03) was extremely related with shorter OS in patients. ConclusionOur findings from public databases provided a unique insight into expression characteristics and prognostic values of CXCR members in LUAD, which would be benefit for the understanding of pathogenesis, diagnosis, prognosis prediction and targeted treatment in LUAD.

2021-04-01·SLAS Discovery4区 · 生物学

Development of a Novel SNAP-Epitope Tag/Near-Infrared Imaging Assay to Quantify G Protein-Coupled Receptor Degradation in Human Cells

4区 · 生物学

Article

作者: Marsh, Nicole M ; Lee, Kyung-Soon ; Hague, Chris ; Navaluna, Edelmar ; Janezic, Eric M

We have developed a novel reporter assay that leverages SNAP-epitope tag/near-infrared (NIR) imaging technology to monitor G protein-coupled receptor (GPCR) degradation in human cell lines. N-terminal SNAP-tagged GPCRs were subcloned and expressed in human embryonic kidney (HEK) 293 cells and then subjected to 24 h of cycloheximide (CHX)-chase degradation assays to quantify receptor degradation half-lives (t_1/2) using LICOR NIR imaging-polyacrylamide gel electrophoresis (PAGE) analysis. Thus far, we have used this method to quantify t_1/2 for all nine adrenergic (ADRA1A, ADRA1B, ADRA1D, ADRA2A, ADRA2B, ADRA2C, ADRB1, ADRB2, ADRB3), five somatostatin (SSTR1, SSTR2, SSTR3, SSTR4, SSTR5), four chemokine (CXCR1, CXCR2, CXCR3, CXCR5), and three 5-HT2 (5HT2A, 5HT2B, 5HT2C) receptor subtypes. SNAP-GPCR-CHX degradation t_1/2 values ranged from 0.52 h (ADRA1D) to 5.5 h (SSTR3). On the contrary, both the SNAP-tag alone and SNAP-tagged and endogenous β-actin were resistant to degradation with CHX treatment. Treatment with the proteasome inhibitor bortezomib produced significant but variable increases in SNAP-GPCR protein expression levels, indicating that SNAP-GPCR degradation primarily occurs through the proteasome. Remarkably, endogenous β2-adrenergic receptor/ADRB2 dynamic mass redistribution functional responses to norepinephrine were significantly decreased following CHX treatment, with a time course equivalent to that observed with the SNAP-ADRB2 degradation assay. We subsequently adapted this assay into a 96-well glass-bottom plate format to facilitate high-throughput GPCR degradation screening. t_1/2 values quantified for the α₁-adrenergic receptor subtypes (ADRA1A, ADRA1B, ADR1D) using the 96-well-plate format correlated with t_1/2 values quantified using NIR-PAGE imaging analysis. In summary, this novel assay permits precise quantitative analysis of GPCR degradation in human cells and can be readily adapted to quantify degradation for any membrane protein of interest.

项与 CXCR5 x CXCR3 x CXCR2 x CXCR1 相关的新闻（医药）

2024-08-11

·佰傲谷BioValley

错综复杂的趋化因子

趋化因子系统参与调节细胞迁移、粘附、定位和细胞间相互作用，作用于肿瘤细胞和免疫细胞调节二者细胞活动，高度参与肿瘤的发展过程。根据肿瘤发生过程中所处的阶段、免疫细胞的活化状态、效应与调控反应间的平衡以及趋化因子受体在效应靶细胞和调节性靶细胞上的相对表达，趋化因子会表现出促肿瘤和抗肿瘤两种效应，甚至同一趋化因子作用于不同细胞，具有两种截然相反的效应。一、促瘤趋化因子 1. CCL2：通过CCL2-CCR2轴募集肿瘤相关免疫抑制细胞；介导肿瘤与肿瘤相关巨噬细胞（TAM）相互作用，提高肿瘤干细胞特性、转移能力和治疗抵抗。 2. CXCL1/CXCL8：通过CXCL1/CXCL8-CXCR2轴募集肿瘤相关免疫抑制细胞。 3. CXCL12：通过CXCR4-CXCL12轴促进TAM分化为血管周围TAM细胞，提高血管通透性，使肿瘤细胞向血管内浸润；实体瘤增加骨髓基质细胞中CXCL12的表达，导致表达CXCR4的髓样细胞积聚，影响免疫细胞的发育成熟，CXCR4-CXCL12轴参与Treg向骨髓的迁移。 4. CCR4：在肿瘤微环境（TME）中募集调节性T细胞（Treg）。 5. CCR6：促进Treg细胞在TME原位增殖。 6. CCR8：在TME内DC细胞附近募集Treg，并通过抗原识别使Treg具有免疫抑制作用；通过CCR8-CCL1轴增加Foxp3表达维持Treg细胞的免疫抑制能力。 7. CCR4+Th2、CCR6+Th17、CXCR3+Th1、CXCR5+Tfh，以上4类趋化因子受体分别在不同细胞中的表达，与Treg抑制功能有一定相关性。二、抗瘤趋化因子 1. XCL1：通过XCL1-XCR1轴介导cDC1细胞向肿瘤募集，促进cDC1与CD8+T细胞相互作用，促使T细胞扩增和获得效应器功能。 2. CXCL11：其表达与髓源性抑制细胞（MDSCs）的丰度和CD8+T细胞浸润程度成反比。 3. CCR7：介导cDC1和cDC2细胞从肿瘤向TDLN迁移，启动T细胞的效应功能。 4. CCL21：介导T细胞和DC细胞向肿瘤引流淋巴结（TDLN）募集，其表达减少会影响免疫细胞群定位，最终可能导致T细胞活性降低。 5. CX3CR1：CD8+T细胞接收到CX3CR1信号才能发挥抗肿瘤作用。三、双效趋化因子 1. CCR5：CCR5-CCL5轴介导cDC1向肿瘤募集，能同时募集Treg细胞和CD8+T细胞；调控TAM表型和功能，介导肿瘤与TAM相互作用，提高肿瘤肝细胞性、转移能力、治疗抵抗 2. CXCR3：CXCR3-CXCL9/CXCL10轴也能同时募集Treg和CD8+T细胞；使干细胞样TCF-1+细胞向cDC1细胞募集、在TME中重激活和通过接触IL-2获得效应器功能；调控免疫效应细胞在肿瘤附近的定位。四、药物开发一些趋化因子的研究进入了临床阶段，但总体而言疗效不显著。 1. CXCR3-CXCL9/10/11：IFN-γ是该趋化因子轴的主要驱动因素，联用可以增加效应细胞浸润；瘤内注射CXCL9/10/11等配体或者表达配体的溶瘤病毒，增加效应细胞浸润。 3. CXCR4：使用其拮抗剂 AMD3100， BL-8040可以促进肿瘤的T细胞浸润。 4. CCR4-CCL22/17：用于阻断该轴介导的Treg募集的策略，包括阻断抗体、siRNAs和拮抗剂：（1）CCR4抗体：mogamulizumab (KW-0761)是一种人源化、糖工程IgG1κ单克隆抗体，通过ADCC靶向表达CCR4的细胞。临床试验结果显示它可以消除淋巴瘤中Treg的积累。（2）CCR4小分子抑制剂：FLX475和RPT193，FLX475联合派姆单抗治疗晚期或转移性癌症的1/2期临床试验(NCT03674567)最近已经完成，但尚未被报道；此外GSK 的(GSK2239633) 和AstraZeneca的(AZD-1678，AZD-2098) 也是CCR4的小分子抑制剂。 5. CCL2-CCR2：阻断CCL2-CCR2，可以抑制MDSCs的浸润：（1）抗CCR2抗体：MLN1202，治疗骨转移（NCT01015560）。（2）CCR2小分子抑制剂：PF-04136309，联合白蛋白-紫杉醇/吉西他滨治疗中期静态PDA患者的1b期试验显示，外周血中炎症性单核细胞(IM)减少，而没有在骨髓中积累。但与标准化疗相比，CCR2抑制也会导致肺毒性增加。在另一项1b期试验中PF-04136309和叶酸，不同的标准化疗方案（边缘可切除和局部晚期胰腺癌），是安全的，减少单核细胞从骨髓，TAM浸润原发肿瘤，导致高于预期的客观反应率（49%）。（3）CCR2拮抗剂：CCX872 ，用于治疗胰腺癌，总生存率提高（18个月时29%Vs18.6%）。 6. CCR5：CCR5拮抗剂Maraviroc，在体外模型中将巨噬细胞重新极化为免疫活性表型。目前还在招募的临床试验是卒中后认知障碍：NCT04966429 Safety and Efficacy of Maraviroc in Post-stroke Cognitive Impairment Phase2 7. CXCR1/CXCR2-CXCL8：阻断该轴，抑制肿瘤生长：（1）CXCR1/2抑制剂：Reparixin是一种临床级抑制剂，可在体外抑制乳腺癌的生长。（2）CXCR1/2的小分子拮抗剂：包括SCH479833和SCH527123，在乳腺癌、CRC、自发性结肠癌肝转移和黑色素瘤的异种移植模型中具有抗肿瘤活性。（3）CXCL8阻断抗体：ABX-CXCL8，在异种移植模型中抑制黑色素瘤的生长。总体如麻省总医院Andrew D. Luster教授所言，趋化因子和趋化因子受体很难作为治疗靶点进行开发... Even if chemokines and chemokine receptors represent difficult therapeutic targets, they might help todissect cellular components critical for induction and maintenance of pro- and anti-tumorigenic immune cell states. 参考文献 Hanahan, D. et al. Hallmarks of cancer: the next generation. Cell. 2011; 144: 646-674. Hua, Y. et al. Tumors vs. chronic wounds: an immune cell’sperspective. Front. Immunol. 2019; 10: 2178. Villablanca et al, Tumor-mediated liver X receptor-alpha activation inhibits CC chemokine receptor-7expression on dendritic cells and dampens antitumor responses. Nat. Med. 2010; 16: 98–105. Binnewies, M. et al, Unleashing type-2 dendritic cells to drive protective antitumor CD4(+) T cell immunity. Cell. 2019; 177: 556–571.e16. Griffith, J.W. et al. Chemokines and chemokinereceptors: positioning cells for host defense and immunity. Annu. Rev. 2014; 32: 659-702. Karan Kohli et al，Key chemokines direct migration of immune cells in solid tumors，Cancer Gene Ther . 2022;29(1):10-21. 本周好文推荐如需转载请联系佰傲谷并在醒目位置注明出处 · · · · · · · ·

免疫疗法临床申请

2023-11-15

·BioSpace

GeneTex Augments Its GPCR Reagent Portfolio With a Highly Specific CXCR2 Recombinant Monoclonal Antibody

IRVINE, CA / ACCESSWIRE / November 15, 2023 / GeneTex, a multinational antibody manufacturer, announces a new addition to its growing product line of validated recombinant monoclonal antibodies against G protein-coupled receptors (GPCRs). CXC motif chemokine receptor 2 (CXCR2) belongs to the family of 20 human chemokine receptors responsible for signal transduction triggered by the binding of one or more of 46 chemokines. Chemokines and their respective receptors, which normally are involved in the immune response, are also active in a plethora of diseases, including inflammatory and autoimmune disorders, neurological disease, and solid and hematologic cancers, among others. Though there is a significant body of literature on chemokines, there are fewer studies on the receptors. Novel reagents that are specific for particular CXC (and other chemokine) receptors are essential to promote additional research. CXCR2 Antibody [HL2604] Validation CXCR2 Antibody [HL2604] testing on GPCR array, IHC analysis, and Western blot analysis. Human GPCRs are expressed by over 820 genes that code for highly dynamic, seven-transmembrane domain proteins that respond to ligands of various types. GPCRs elicit profound physiological and pathophysiological effects that are relevant to many chronic diseases, including type 2 diabetes mellitus, malignancies, mood disorders, obesity, and neurodegenerative disease. Approximately 350 of the non-olfactory GPCRs are considered amenable to pharmaceutical intervention, though the vast majority remain without available drugs. Research into GPCR biology is of great importance, and GeneTex is committed to producing a comprehensive GPCR antibody portfolio to promote this work. Due to well-known technical challenges associated with antibody development for specific GPCR targets, GeneTex employs enhanced and/or novel validation modalities to establish specificity among GPCR family members, particularly those that share sequence identity. These strategies include knockout/knockdown testing, immunohistochemistry (IHC) or immunocytochemistry (ICC/IF) staining of tissues/cells with differential target expression, and comparison of signals between antibodies against the same target, among other approaches. In addition, GeneTex is incorporating the innovative VirDTM-GPCR arrays (CDI Labs, Baltimore, MD) to determine specificity. In the case of the new recombinant monoclonal CXCR2 antibody (GTX639056), this array demonstrates absolute specificity for CXCR2, with no cross-reactivity detected for CXCR1, CXCR3, CXCR4, CXCR5, and CXCR6. This is particularly significant as CXCR1 and CXCR2 share the highest similarity with ~77% sequence identity. This array data is complemented by both western blot (WB) and IHC validation. As expected, the WB shows a significantly more robust signal in a "membrane extract" fraction compared to the matching "whole cell extract" sample. For IHC, human pancreatic cancer tissue staining reveals the anticipated signal enrichment in the cytoplasm and at the cell membrane. GeneTex is committed to providing the most extensive and thoroughly validated recombinant monoclonal antibody repertoire for GPCR proteins. For the chemokine receptors specifically, efforts are currently underway to broaden the catalog of reagents against the remaining CXC, CC, CX3C, and XC receptors. This same large-scale approach will be applied to all six families of proteins within the GPCR superfamily. Contact Information Allen Lee Vice President - Business Development allensl@genetex.com (949)553-1900 SOURCE: GeneTex, Inc. View source version on accesswire.com: