navarixin (MK-7123) / Merck (MSD), Ligand - LARVOL DELTA

Tumor-associated neutrophils in lung adenocarcinoma: from mechanisms to therapeutic targeting. (PubMed, Front Immunol) - "Furthermore, we evaluate current therapeutic strategies targeting TANs, such as CXCR1/2 inhibitors (SX-682, Navarixin), PAD4 inhibitors (Cl-amidine), NET-degrading enzymes (DNase I), TGF-β inhibitors (Galunisertib), and myeloid modulators, with a focus on LUAD-specific preclinical and clinical evidence. Major challenges, including off-target toxicity, infection risk, and the lack of predictive biomarkers, are discussed. By bridging mechanistic insights with translational opportunities, this review provides a framework for developing neutrophil-targeted combination therapies to overcome immunotherapy resistance in LUAD."

IO biomarker • Journal • Review • Infectious Disease • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CXCR1 • CXCR2 • IFNG • TGFB1

Novel Squaramides and Squaramates Containing a Five-Membered Heterocyclic Ring: Synthesis, Structure, and Cytotoxicity. (PubMed, Int J Mol Sci) - "Compound 3d exhibited the most pronounced improvement (five-fold) over Navarixin in HL-60 cells 5.81 µM, while compounds 3a and 3c demonstrated superior potency and selectivity in A-549 cells (10.33 µM and 9.65 µM). These findings identify squaric acid derivatives as promising candidates for further anticancer drug development and structure-activity relationship studies."

Journal • Oncology

Tumor-educated macrophages promote cytokine-driven lung colonization in triple-negative breast cancer. (PubMed, Oncoimmunology) - "Pharmacological inhibition of CCR5, CXCR2, and IL1R1 with maraviroc, navarixin, and anakinra, respectively, disrupted this cytokine axis, suppressing metastatic colonization in vivo. Our findings reveal that blocking cytokine receptor signaling disrupts the pro-metastatic crosstalk between macrophages and TNBC cells, offering a clinically actionable strategy to restrain metastasis and overcome therapy resistance in TNBC."

Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CCL3 • CD4 • FOXP3 • IL1B • IL1R1

CCR7 expression and spatial distribution in inflammatory breast cancer: A baseline characterization for therapeutic targeting (AACR 2026) - "Functional studies included the CCR7 antagonist Navarixin, CCL19/21-induced migration assays, and generation of CCR7 CRISPR knockout clones. CCR7 CNAs occurred in both IBC and non-IBC but did not correlate with mRNA or protein levels... CCR7 expression in IBC is independent of copy number and supported by a ligand-rich microenvironment that positions CCR7⁺ tumor cells along lymphatics. Integrated genomic, spatial, and functional data support CCR7 as a therapeutic target in IBC, with studies ongoing."

Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Inflammatory Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CCL19 • CCL21 • CCR7 • CD163 • HER-2 • PDPN

ChemoNETosis is associated with chemotherapy resistance in pancreatic cancer (AACR 2025) - "NETs may play a key role in chemotherapy resistance in pancreatic cancer. Targeting NETs could provide a novel approach to enhancing the efficacy of chemotherapy in preclinical models and warrants further investigation."

Breast Cancer • Oncology • Pancreatic Cancer • Solid Tumor

NR4A2 induces perineural invasion in head and neck squamous cell carcinoma and pancreatic ductal adenocarcinoma via CXCL5/CXCR2 signaling axis. (PubMed, Cancer Lett) - "Further treatment with CXCL5 ligand significantly induced neuritogenesis, while the neurite outgrowth was abrogated when cotreated with CXCR2 (receptor for CXCL5) inhibitor SCH527123...NR4A2 knockdown in UMSCC1 cells impaired tumor formation in vivo, and the xenograft tissues exhibited significant downregulation of CXCL5, providing direct in vivo evidence for the NR4A2-CXCL5 axis in tumor progression. NR4A2 is a key driver of CXCL5-mediated PNI and the NR4A2/CXCL5/CXCR2 signaling axis is a potential therapeutic target in HNSCC and PDAC."

Journal • Head and Neck Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • CCL2 • CXCL5 • CXCR2 • NR4A2 • RAC1 • TIMP2

CXCR2 antagonism as a promising therapeutic approach for pulmonary fibrosis therapy. (PubMed, Biomed Pharmacother) - "In this study, we evaluated and compared the anti-inflammatory effects of four CXCR2 antagonists - DF2755A, AZD-5069, SX-682, and SCH527123 - in a murine model of bleomycin-induced lung injury. Importantly, DF2755A and SX-682 were particularly effective in mitigating fibrosis and chronic inflammatory changes when administered in both preventive and therapeutic schedules, even at later stages of disease progression. These findings underscore the potential of CXCR2 antagonism, especially with DF2755A, as a promising strategy to limit inflammation and fibrosis in experimental lung injury."

Journal • Fibrosis • Immunology • Inflammation • Pneumonia • Pulmonary Disease • Respiratory Diseases • CXCR2 • MPO

Unlocking the Power of CXCR2 Inhibition to Overcome Gemcitabine Resistance in Pancreatic Cancer. (PubMed, FASEB Bioadv) - "We treated parental and GemR cell lines with gemcitabine in combination with a CXCR2 antagonist, Navarixin. In conclusion, these findings highlight the critical role of the CXCR2 axis in PDAC therapy resistance. Targeting CXCR2 enhances gemcitabine efficacy, offering a potential therapeutic strategy to overcome resistance in PDAC."

Journal • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • CXCL1 • CXCL5 • CXCL8 • CXCR2 • ITGB2

CXCR4 antagonism corrects neutrophil abnormalities and reduces pneumonia severity in a pharmacological mouse model of CXCR2 loss-of-function-mediated neutropenia. (PubMed, Front Immunol) - "Mavorixafor, an orally bioavailable CXCR4 antagonist, has shown meaningful increases in absolute neutrophil count and reduced infections in WHIM syndrome patients...Mice received the CXCR2 antagonist navarixin orally and then the CXCR4 antagonist compound 1 or vehicle control daily for 7 days...Our findings provide evidence that oral administration of a CXCR4 antagonist can effectively correct blood and BM neutrophil abnormalities and reduce infection susceptibility in a CXCR2 LOF mouse model. These findings suggest potential therapeutic benefits of CXCR4 antagonist therapy in addressing peripheral blood neutropenia and other pathogenic phenotypes in patients with CXCR2 LOF variants."

Journal • Preclinical • Dermatology • Hematological Disorders • Infectious Disease • Neutropenia • Pneumococcal Infections • Pneumonia • Respiratory Diseases • CXCR2

CXCR4 antagonism reduces pneumonia severity in a pharmacological mouse model of CXCR2 loss-of-function-mediated neutropenia. (ASH 2025) - "Mavorixafor, an oralCXCR4 antagonist, has demonstrated a clinical benefit that includes increased neutrophil count andconcomitant reductions in infections for WHIM patients5...The current study aims to address these criticalquestions.MethodsFemale BALB/c mice (10-15 per group) were administered the CXCR2 antagonist navarixin (3 mg/kg) viaoral gavage, followed by daily doses of the CXCR4 antagonist X4P-002 (10 mg/kg) or a vehicle control for 4or up to 14 days, administered two hours after the navarixin dose...Notably, CXCR4 antagonism reduces the severity of pneumonia,likely associated with the normalization of neutrophil counts in infected tissues. In conjunction with ourprevious findings6, which showed that CXCR4 antagonism corrected blood and BM neutrophilabnormalities as well as reduced BM myelokathexis frequency, our data provide strong support forCXCR4 antagonist therapy as a promising treatment strategy for patients with CXCR2 LOF."

Preclinical • Dermatology • Hematological Disorders • Immunology • Infectious Disease • Neutropenia • Pneumococcal Infections • Pneumonia • Primary Immunodeficiency • Respiratory Diseases • CXCR2

The CXCR1 as a putative marker for cancer stem cell-like phenotypes in chemotherapy-resistant pancreatic ductal adenocarcinoma. (PubMed, Am J Cancer Res) - "Combination treatment with gemcitabine and Navarixin, a CXCR1 inhibitor, significantly reduced expression of CXCR1, CXCL6, and CSC/EMT markers in vitro. In vivo, tumors treated with the combination therapy showed markedly lower CXCR1 and CXCL6 expression than other treatment groups. These findings indicate that the CXCR1 axis supports CSC maintenance in PDAC, and that co-targeting CSC and non-CSC populations may improve therapeutic outcomes."

Journal • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • CXCL6 • CXCR1

CXCR4 Antagonism Corrects Peripheral Neutropenia and Mature Neutrophil Accumulation in Bone Marrow in a Pharmacological Mouse Model of CXCR2 Loss-of-Function (ASH 2024) - "Additional clinical manifestations in patients with WHIM syndrome may include warts, hypogammaglobulinemia and lymphocytopenia.1,2 Interestingly, patients with loss-of-function (LoF) variants in CXCR2 display phenotypic features similar to those observed in patients with WHIM syndrome, such as neutropenia, increased infection susceptibility, and myelokathexis.3,4 Mavorixafor, an orally bioavailable CXCR4 antagonist, has demonstrated clinically meaningful increases in absolute neutrophil and lymphocyte counts and concomitant reductions in infections in patients aged 12 years and older with WHIM syndrome, leading to its recent approval by the U.S. Food and Drug Administration.5 Whether CXCR4 antagonist therapy can similarly correct the common pathogenic phenotypes observed in patients with CXCR2 LoF variants as are seen in patients with WHIM syndrome has yet to be determined...Methods Female BALB/c mice (6 mice per group) were dosed with the CXCR2 antagonist navarixin (3..."

Preclinical • Dermatology • Hematological Disorders • Immunology • Infectious Disease • Neutropenia • Primary Immunodeficiency • CXCR2

Repurposing of Chemokine Antagonists for Combined Phase-Resolved Spinal Cord Injury Treatment. (PubMed, Adv Sci (Weinh)) - "The effects of mogamulizumab and chemical antagonists of C-C/C-X-C chemokine receptors TAK-799, SB225002, and MK-7123 on SCI recovery in rodents are further estimated. Here blockade of CCR5 and CXCR1/2 chemokine receptors is shown beneficial for amelioration of acute SCI, whereas anti-CCR4 antibody mogamulizumab readily prevents secondary inflammation in the injured area. Summarizing, the current report claims for a novel combined time-resolved therapeutic modality in SCI treatment, which supports feasibility and motivates off-label clinical evaluation in appropriate cohorts."

Journal • CNS Disorders • Oncology • Orthopedics • CCL2 • CCL22 • CCR4 • CX3CL1 • CXCL1 • CXCR1 • IL2 • IL6 • IL7 • TNFA

Potential of CXCR1/2 as a target for the treatment of inflammation and cancer (Review). (PubMed, Exp Ther Med) - "Therefore, SCH527123 represents a new drug candidate with potential in the fields of inflammation and cancer. Although challenges remain in translating preclinical findings into clinical benefits, ongoing research and development efforts on using SCH527123 hold promise for improving the survival and quality of life of patients with these devastating diseases."

Journal • Review • Asthma • Chronic Obstructive Pulmonary Disease • Immunology • Oncology • Ovarian Cancer • Pancreatic Cancer • Pulmonary Disease • Respiratory Diseases • Solid Tumor • CXCL8 • CXCR1 • CXCR2

The Interleukin-8-CXCR1/2 Axis as a Therapeutic Target in Peritoneal Carcinomatosis. (PubMed, Curr Oncol) - "IL-8 targeting agents such as monoclonal antibodies (BMS-986253) and small-molecule inhibitors (SX-682, AZD5069, navarixin) have shown efficacy in mitigating tumor growth and improving the efficacy of immune checkpoint inhibitors. In this review, we discuss the influence of the IL-8/CXCR1/CXCR2 axis within the peritoneal immune environment in PC and highlight recent work using IL-8 or CXCR1/CXCR2 blockade as a therapeutic strategy for PC. Continued research into the peritoneal immune microenvironment and the development of targeted therapies are essential for improving the management and prognosis of PC, potentially enhancing antitumor immunity and patient outcomes."

Journal • Review • Oncology • Peritoneal Cancer • CXCL8 • CXCR1 • CXCR2 • IL6

Gemcitabine-induced neutrophil extracellular traps via interleukin-8-CXCR1/2 pathway promote chemoresistance in pancreatic cancer. (PubMed, Br J Cancer) - "Our findings reveal that NETs contribute to chemoresistance in PDAC and that IL-8-mediated chemoNETosis plays a pivotal role in this process. Inhibition of CXCR1/2-mediated NET formation enhances the efficacy of GEM. This approach may represent a promising therapeutic strategy for overcoming chemoresistance in PDAC. These results support further clinical investigation of anti-NETs therapies."

Journal • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • CXCL8 • CXCR1

Deciphering the Role of IL-8/CXCR2 in CD47 Regulation and Macrophage Infiltration: Potential Therapeutic Insights (UAA 2025) - "Tumor-bearing mice treated with the CXCR2 inhibitor Navarixin or CD47 inhibitor CC-90002 exhibited a significant reduction in tumor growth compared to control groups. Collectively, these results suggest that blocking the IL-8/CXCR2 and CD47 pathways can reverse immune evasion mechanisms and restore the anti-tumor activity of macrophages. (a) Immunohistochemical staining (IHC) for CXCR2, IL-8, CD 47 expression and the infiltration of TAM in benign, adenocarcinoma, Castration-Resistant Prostate Cancer (CRPC) and Neuroendocrine Prostate Cancer (NEPC) patient tissue samples, the black ba (a-b) Mice experiment diagrammatic drawing and tumor size in several tumor-bearing mice models; (c) Tumor associated macrophages (CD11b+F4/80+) identified by flow cytometry from tumors collected from mice bearing tumours constructed by different cell (a) The migration ability of macrophages after activation of the IL-8/CXCR2 pathway, the black bars in the images represent 200 µm; (b)..."

Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Neuroendocrine Tumor • Prostate Cancer • Solid Tumor • CD47 • CXCL8 • CXCR2 • ITGAM

Biased antagonism of a series of bicyclic CXCR2 intracellular allosteric modulators. (PubMed, Front Pharmacol) - "These antagonists likely bind to a conserved intracellular pocket that is also targeted by the well-known CXCR2 antagonist, navarixin...Furthermore, a detailed statistical analysis revealed an additional bias in the inhibition profiles dependent on the specific ELR+ chemokine used to stimulate the receptor. Altogether, these results describe the MVH compounds as the first set of biased CXCR2 intracellular antagonists."

Journal • Oncology • CXCR2

Unlocking the Power of CXCR2 Inhibition to Overcome Gemcitabine Resistance in Pancreatic Cancer. (PubMed, bioRxiv) - "In both parental and GemR xenograft models, combination therapy with Navarixin (a CXCR2 antagonist) and gemcitabine demonstrated superior antitumor and antimetastatic activity compared to either treatment alone. In conclusion, these findings highlight the critical role of the CXCR2 axis in PDAC therapy resistance. Targeting CXCR2 enhances gemcitabine efficacy, offering a potential therapeutic strategy to overcome resistance in PDAC."

Journal • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • CXCL1 • CXCL5 • CXCL8 • CXCR2 • ITGB2

The CXCL1-CXCR2 Axis as a Component of Therapy Resistance, a Source of Side Effects in Cancer Treatment, and a Therapeutic Target. (PubMed, Cancers (Basel)) - "It discusses anti-CXCL1 antibodies and CXCR2 antagonists, including AZD5069, SB225002, SCH-479833, navarixin/SCH-527123, ladarixin/DF2156A, and reparixin, as well as strategies to enhance CXCR2 expression in lymphocytes during adoptive cell therapy to improve immunotherapy outcomes. CXCR2 inhibitors are well tolerated by patients in clinical trials. However, the limited number of studies evaluating these agents in combination with standard chemotherapy precludes any definitive conclusions."

Adverse events • IO biomarker • Journal • Review • Cardiovascular • Oncology • Pain • CXCL1 • CXCL8 • CXCR2

Navarixin alleviates cardiac remodeling after myocardial infarction by decreasing neutrophil infiltration and the inflammatory response. (PubMed, Front Pharmacol) - "Through transcriptomic analysis, we found that Nav affects signaling pathways such as the innate immune response and the chemokine signaling pathway, thereby decreasing the inflammatory response by reducing neutrophil chemotaxis. This study provides new insights for the use of CXCR2 inhibitors as new therapeutic options for myocardial infarction in the future."

Journal • Atherosclerosis • Cardiovascular • Coronary Artery Disease • Fibrosis • Heart Failure • Immunology • Inflammation • Myocardial Infarction • CXCR2 • MPO

Structure-activity relationship study of navarixin analogues as dual CXCR2 and CCR7 antagonists. (PubMed, Bioorg Chem) - "Additional systematic structural variations afforded various squaramide analogues that displayed potent CCR7 antagonism in a calcium mobilization assay with IC50 values in the low nM range. Unfortunately, the same compounds also displayed potent CXCR2 antagonistic activity and should therefore be considered as dual CCR7/CXCR2 antagonists."

Journal • Immunology • Oncology • CCR7 • CXCR2

Angiopoietin-2 regulates the phenotypic switch of vascular smooth muscle cells. (PubMed, FASEB J) - "Lipid peroxidation inhibition by ferrostatin-1 or the IL-8 receptor antagonist navarixin inhibited the Ang-2-induced migration...Ang-2 dysregulation may disrupt spiral artery remodeling and contribute to preeclampsia. Ang-2 may be a novel therapeutic target for the treatment of pregnancy complications affected by incomplete spiral artery remodeling."

Journal • Gynecology • ATG7 • CXCL8

A Fluorescent Probe Enables the Discovery of Improved Antagonists Targeting the Intracellular Allosteric Site of the Chemokine Receptor CCR7. (PubMed, J Med Chem) - "The thiadiazoledioxide 10 was derived from the CCR7 antagonist Cmp2105 by removing a methyl group from the benzamide moiety, while the squaramide 21m was obtained from the CXCR1/CXCR2 antagonist and clinical candidate navarixin by replacing the ethyl substituent by a tert-butyl group to engage a lipophilic subpocket. We show that 10 and 21m qualify to probe CCR7 biology in recombinant and primary immune cells and expect our novel probes to facilitate the design of next-generation intracellular CCR7 ligands."

Journal • CCR7 • CXCR1 • CXCR2

CCL21-CCR7 blockade prevents neuroinflammation and degeneration in Parkinson's disease models. (PubMed, J Neuroinflammation) - "Finally, we demonstrated that navarixin, a clinically relevant chemokine inhibitor with high affinity for the CCR7 receptor, could block CCL21 effects on microglia and prevent neurodegeneration and behavioral deficits in two mouse models of PD induced with either α-synuclein oligomers (αSynO) or 3,4-dihydroxyphenylacetaldehyde (DOPAL). Altogether, our data indicate that navarixin blocks CCL21/CCR7-mediated neuron-microglia communication and could be used as a therapeutic strategy against PD."

Journal • CNS Disorders • Inflammation • Movement Disorders • Parkinson's Disease • CCL21 • CCR7