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

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

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

Complement C3 of tumor-derived extracellular vesicles promotes metastasis of RCC via recruitment of immunosuppressive myeloid cells. (PubMed, Proc Natl Acad Sci U S A) - "Notably, targeting the CCL2/CCR2 or CXCL1/CXCR2 axis with the inhibitors RS504393 or Navarixin, respectively, effectively suppresses lung metastasis induced by RCC-derived C3 in a mouse model. Clinically, RCC patients with high expression of C3 demonstrate poor prognosis. Collectively, our findings reveal that tumor-derived EV C3 induces an immunosuppressive tumor microenvironment via TAMs, and thus promoting RCC metastasis."

Journal • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • CCL2 • CCR2 • CXCL1 • CXCR2

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

Squaric acid derivatives with cytotoxic activity- a review. (PubMed, Chem Biol Interact) - "On the other hand, squaric acid derivative-Navarixin, has already been evaluated in Phase II clinical trials for its potential efficacy in the treatment of solid tumors. In this context this review is the first looking into the potential applications of squaric acid derivatives as anticancer therapies. It analyzes experimental studies presented in articles published between 2000 and 2024."

Journal • Review • Breast Cancer • Cervical Cancer • Colorectal Adenocarcinoma • Colorectal Cancer • Gastric Cancer • Oncology • Solid Tumor

1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol treatment inhibits abnormal tumor growth by regulating neutrophil infiltration in a non-small cell lung carcinoma mouse model. (PubMed, Biomed Pharmacother) - "PLAG had a significantly higher tumor growth inhibitory effect and survival rate than other neutrophil infiltration-targeting inhibitors (e.g., Navarixin, lymphocyte antigen 6 complex locus G6D antibody [aLy6G])...PLAG-mediated inhibition of neutrophil infiltration enhances the efficacy of immune checkpoint inhibitors (ICIs), increasing the antitumor efficacy and survival rate by 30 %. In conclusion, PLAG could be a novel alternative to anti-tumor drugs that effectively targets excessive neutrophil infiltration into cancer tissues."

IO biomarker • Journal • Preclinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • LY6G6D • TXNIP

Development of a NanoBRET Assay Platform to Detect Intracellular Ligands for the Chemokine Receptors CCR6 and CXCR1. (PubMed, ChemMedChem) - "By means of these studies we identified compound 10, a previously reported tert-butyl analogue of navarixin, as a low nanomolar intracellular CCR6 antagonist. Further, our assay platform clearly indicated intracellular binding of the CCR6 antagonist PF-07054894, currently evaluated in phase I clinical trials for the treatment of ulcerative colitis, thereby providing profound evidence for the existence and the pharmacological relevance of a druggable IABS at CCR6."

Journal • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • Oncology • Pulmonary Disease • Respiratory Diseases • Ulcerative Colitis • CCR6 • CXCR1 • CXCR2

Lactate-induced activation of tumor-associated fibroblasts and IL-8-mediated macrophage recruitment promote lung cancer progression. (PubMed, Redox Biol) - "Furthermore, we observed that the use of IL-8 receptor antagonists, SB225002, or Navarixin, significantly reduced TAM infiltration and enhanced the therapeutic efficacy of anti-PD-1 or anti-PD-L1 treatment. This finding indicates that inhibiting IL-8R activity can attenuate the impact of CAFs on the tumor microenvironment, thus restraining the progression of lung cancer."

Journal • Lung Cancer • Oncology • Solid Tumor • CAFs • CXCL8 • FRA1 • JUNB • NUSAP1

Senescent Fibroblasts Potentiate Peritoneal Metastasis of Diffuse-type Gastric Cancer Cells via IL-8-mediated Crosstalk. (PubMed, Anticancer Res) - "sCAFs promote peritoneal metastasis of DGC via IL-8-mediated crosstalk."

Journal • Gastric Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • CAFs • CXCL8

Sharing our just published basket study of the CXCR2 inhibitor navarixin plus pembrolizumab in MCRPC, CRC, & NSCLC. Low activity likely due to insufficient PD effect and MDSC suppression unfortunately….

CXCR2 antagonist navarixin in combination with pembrolizumab in select advanced solid tumors: a phase 2 randomized trial. (PubMed, Invest New Drugs) - P2 | "Safety and tolerability of the combination were manageable. (Trial registration: ClinicalTrials.gov , NCT03473925)."

Combination therapy • Journal • Metastases • P2 data • Castration-Resistant Prostate Cancer • Colorectal Cancer • Gastrointestinal Cancer • Genito-urinary Cancer • Hematological Disorders • Hepatology • Lung Cancer • Metastatic Castration-Resistant Prostate Cancer • Neutropenia • Non Small Cell Lung Cancer • Oncology • Pneumonia • Prostate Cancer • Solid Tumor • CXCR2

CXCR2-Blocking Has Context-Sensitive Effects on Rat Glioblastoma Cell Line Outgrowth (S635) in an Organotypic Rat Brain Slice Culture Depending on Microglia-Depletion (PLX5622) and Dexamethasone Treatment. (PubMed, Int J Mol Sci) - "Our method allowed us to study the influence of three different factors-dexamethasone, PLX5622, and CXCL2-in a well-controlled, simplified, and straight-forward mechanistic manner, and at the same time in a more realistic ex vivo scenario compared to in vitro studies. In our model, we showed a GBM outgrowth enhancing synergism between CXCR2-blocking and Dex-treatment in the native condition, which was levelled by PLX5622-pretreatment."

Journal • Preclinical • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • CSF1 • CXCR2

Prevention by the CXCR2 antagonist SCH527123 of the calcification of porcine heart valve cusps implanted subcutaneously in rats. (PubMed, Front Cardiovasc Med) - "The calcification of GA-fixed porcine aortic valve cusps implanted subcutaneously in rats was significantly prevented by antagonizing CXCR2 with SCH527123. This effect may partly result from an inhibition of the GA-induced infiltration of T-cells and macrophages into the xenograft."

Journal • Preclinical • Inflammation • Transplantation • CD68 • CXCR2

Design, Synthesis, and Application of Fluorescent Ligands Targeting the Intracellular Allosteric Binding Site of the CXC Chemokine Receptor 2. (PubMed, J Med Chem) - "Here, we report the rational design, synthesis, and pharmacological evaluation of a series of fluorescent NAMs, based on navarixin (2), which display high affinity and preferential binding for CXCR2 over CXCR1. We demonstrate their application in fluorescence imaging and NanoBRET binding assays, in whole cells or membranes, capable of kinetic and equilibrium analysis of NAM binding, providing a platform to screen for alternative chemophores targeting these receptors."

Journal • Oncology • Pulmonary Disease • Respiratory Diseases • CXCR1

Aortic valve calcification is promoted by interleukin-8 and restricted through antagonizing CXCR2. (PubMed, Cardiovasc Res) - "Overall, these results highlight, for the first time, a significant role for IL-8 in the progression of CAVD by promoting calcification via a CXCR2-- and MMP-12-dependent mechanism that leads to elastin degradation, and identify CXCR2 as a promising therapeutic target for the treatment of CAVD."

Journal • Cardiovascular • Chronic Kidney Disease • Inflammation • Nephrology • Renal Disease • CXCL8 • CXCR2

A Comparative Inflammation-On-A-Chip with A Complete 3D Interface: Pharmacological Applications in COPD-Induced Neutrophil Migration. (PubMed, Adv Healthc Mater) - "We used the IoC model to evaluate the pharmacological effects of CXCR2 inhibitors (MK-7123, AZD5069, and SB225002) on the migration of neutrophil-like cells in the presence of plasma samples from patients with COPD. This is the first study to evaluate inhibitors of CXCR2-dependent NTEM in a comparative IoC model that mimics the physiological 3D microenvironment, consisting of an endothelial barrier, extracellular compartment, and inflammatory conditions. This IoC model will be useful to investigate COPD severity using patient samples, and will aid basic and translational research involving NTEM."

Journal • Chronic Obstructive Pulmonary Disease • Immunology • Inflammation • Pulmonary Disease • Respiratory Diseases

Megakaryocyte-Derived IL-8 Acts as a Paracrine Factor for Prostate Cancer Aggressiveness through CXCR2 Activation and Antagonistic AR Downregulation. (PubMed, Biomol Ther (Seoul)) - "IL-8-induced gene expression changes were suppressed by navarixin, a CXCR1/2 inhibitor, and gallein, a Gβγ inhibitor...The collective findings demonstrate that IL-8 enhances CXCR2 expression, which antagonistically regulates AR expression. More importantly, through changes in IL-8/CXCR2-regulated gene expression, IL-8 induces antiandrogen therapy resistance and epithelial-mesenchymal transition in prostate cancer."

Journal • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • CDH1 • CXCL8 • CXCR1 • CXCR2 • MMP2 • MMP9 • VIM

Senescent Human Pancreatic Stellate Cells Secrete CXCR2 Agonist CXCLs to Promote Proliferation and Migration of Human Pancreatic Cancer AsPC-1 and MIAPaCa-2 Cell Lines. (PubMed, Int J Mol Sci) - "Senescence was induced in primary-cultured human PSCs (hPSCs) through treatment with hydrogen peroxide or gemcitabine...SB225002, a selective CXCR2 antagonist, and SCH-527123, a CXCR1/CXCR2 antagonist, attenuated the effects of conditioned media of senescent hPSCs on the proliferation and migration of pancreatic cancer cells. These results suggest a role of CXCLs as senescence-associated secretory phenotype factors in the interaction between senescent hPSCs and pancreatic cancer cells. Senescent PSCs might be novel therapeutic targets for pancreatic cancer."

Journal • Preclinical • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • CXCL3 • CXCR1 • CXCR2

CXCR1: A novel therapeutic avenue for CSC-like phenotypes in pancreatic ductal adenocarcinoma (AACR 2022) - "We treated with the CXCR1/2 antagonist navarixin at concentrations known to inhibit CXCR1. The population of CXCR1+ cells was higher in the gemcitabine-treated groups. Together, our observations suggest an association between CXCR1 and the CSC-like phenotype in PDAC."

Breast Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • Triple Negative Breast Cancer • ALDH1A1 • CD133 • CD24 • CD44 • CXCL8 • CXCR1 • CXCR4

Combined inhibition of IL‑6 and IL‑8 pathways suppresses ovarian cancer cell viability and migration and tumor growth. (PubMed, Int J Oncol) - "In the present study, the efficacy of co‑targeting IL‑6 and IL‑8 in human ovarian cancer cells by bazedoxifene (Baze) + SCH527123 (SCH) treatment was examined...Baze + SCH also inhibited cell migration and invasion, suppressed ovarian tumor growth and inhibited STAT3 and AKT phosphorylation, as well as survivin expression. Therefore, co‑targeting the IL‑6 and IL‑8 signaling pathways may be an effective approach for ovarian cancer treatment."

Journal • Gynecologic Cancers • Oncology • Ovarian Cancer • Solid Tumor • BIRC5 • STAT3

Identification of the interleukin-8 (CXCL-8) pathway in feline oral squamous cell carcinoma - A pilot study. (PubMed, Can J Vet Res) - "The IL-8 receptor-specific antagonists, Reparixin and SCH527123, were used to identify effects on phosphorylation of these proteins. Due to its potential effects on the tumor microenvironment, in addition to its autocrine effects on Src phosphorylation, the inhibition of the IL-8 receptor may become a beneficial therapeutic tool. Evaluation of the presence of both IL-8 and Src in many cases should elucidate their importance."

Clinical • Journal • Oncology • Oral Cancer • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • CXCL8 • JAK2 • PCR • STAT3