P2, N=40, Terminated, Dompé Farmaceutici S.p.A | Completed --> Terminated; Taking into account that 5 out of 22 patients in the Reparixin group experienced EAD during the first stage of the study, according to the Protocol and the DMC conclusion, it was decided on the early termination of the study

P1, N=15, Not yet recruiting, Roswell Park Cancer Institute | Initiation date: Nov 2024 --> Feb 2025

P2, N=53, Recruiting, Syntrix Biosystems, Inc. | Initiation date: Jun 2024 --> Nov 2024

In mice with pancreatic cancer-induced pain, the microglia activation in the NTS was observed, characterized by increased cell density and decreased process number and length, while injection of microglia inhibitor minocycline in the NTS alleviated pancreatic cancer-induced pain...Blocking CXCL1-CXCR2 signaling by injection of CXCL1 neutralizing antibody or CXCR2 antagonist SB225002 in the NTS of mice with pancreatic cancer-induced pain alleviated abdominal hypersensitivity and hunching behavior, and also reversed the activation of neurons and microglia. Additionally, injection of recombinant CXCL1 in the NTS of sham-operated mice induced abdominal pain, and activated the neurons and microglia. In summary, our study highlights the critical role of NTS microglia activation mediated by CXCL1-CXCR2 signaling in pancreatic cancer-induced pain.

P3, N=409, Terminated, Dompé Farmaceutici S.p.A | Recruiting --> Terminated; The study was stopped due to futility as per protocol

P2, N=140, Recruiting, Eli Lilly and Company | Not yet recruiting --> Recruiting

P2, N=26, Recruiting, Icahn School of Medicine at Mount Sinai | Trial completion date: Mar 2026 --> Dec 2027 | Trial primary completion date: Mar 2025 --> Dec 2025

The combination of the CXCR2 antagonist SB225002 with PD1 blockade and PI improves tumor control and mouse survival. Our results suggest a strategy to reduce RT toxicity and improve the therapeutic index of RT and immune checkpoint combinations.

P2, N=66, Recruiting, Dompé Farmaceutici S.p.A | Trial completion date: May 2025 --> Aug 2025 | Trial primary completion date: Apr 2025 --> Aug 2025

P1, N=15, Not yet recruiting, Roswell Park Cancer Institute

P2, N=140, Not yet recruiting, Eli Lilly and Company

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.

This phenomenon led to increased tumor growth, and conversely, tumor growth decreased when inhibited by the CXCR2 antagonist SB225002. This study unveils how NKX2-1 modulates the infiltration of tumor-promoting neutrophils by inhibiting CXCLs/CXCR2-dependent mechanisms. Hence, targeting CXCR2 in NKX2-1-low tumors is a potential antitumor therapy that may improve LUAD patient outcomes.

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.

Our findings confirm the involvement of the CXCL8/CXCR2-axis in promoting pro-tumorigenic effects in TC cells, further demonstrating its immunotherapeutic significance in human cancer.

Interestingly, treatment with AZD-5069, a CXCR2 inhibitor, attenuates invasion and proliferation of tumor spheroids by blocking direct contact with neutrophils. Our findings also show that CXCR2 inhibition reduces neutrophil migration toward tumor spheroids. These results shed new light on the tumor-promoting mechanisms of human neutrophils and the tumor-suppressive mechanisms of CXCR2 inhibition in pancreatic cancer and may aid in the design and optimization of novel immunotherapeutic strategies based on neutrophils.

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.

P1/2, N=12, Completed, National Cancer Institute (NCI) | Active, not recruiting --> Completed

We conjugate a chemically modified small-molecule inhibitor of MDSC-surface receptor CXCR2 (AZD5069) with polyethylene glycol (PEG) and chemically graft AZD5069-PEG constructs onto amphiphilic polysaccharide derivatives to engineer CXCR2-homing nanoparticles (CXCR2-NP). Encapsulation of JAK2/STAT3i Ruxolitinib (CXCR2-NP Ruxo ) resulted in more durable attenuation in STAT3-regulated arginase activity from PMN-MDSCs and induction of cytolytic T-cell activity vs. free Ruxolitinib in-vitro and in-vivo . Cell-specific delivery of payloads via CXCR2-homing immunonanoparticles represents a novel strategy to disrupt MDSC-mediated immunosuppression and invigorate antitumor immunity in PDAC.

sCAFs promote peritoneal metastasis of DGC via IL-8-mediated crosstalk.

P2, N=53, Recruiting, Syntrix Biosystems, Inc. | Not yet recruiting --> Recruiting

Collectively, our findings highlight the significance of a selective CXCR2+/CD11b+/Gr-1+ subset myeloid cells in favoring the development of CRLM with NAFLD background, and identify a pharmaceutic medicine which is already available for the clinical trials and potential treatment.

However, these effects were reversed by the CXCL2-CXCR2 inhibitor SB225002. In summary, this study suggests that Fn contributes to OSCC progression by promoting tumor cell proliferation, macrophage recruitment, and M2 polarization. Simultaneously, the enhanced CXCL2-mediated crosstalk between OSCC cells and macrophages plays a vital role in the pro-cancer effect of Fn.

P2, N=350, Recruiting, Eli Lilly and Company | Trial completion date: Mar 2026 --> Jul 2026 | Trial primary completion date: Apr 2025 --> Aug 2025

P1/2, N=50, Recruiting, National Cancer Institute (NCI) | Not yet recruiting --> Recruiting

Overall, we demonstrated that TAMs boosted PDAC cell glycolysis through the IL-8/STAT3/GLUT3 signaling pathway. Our cumulative findings suggest that the abrogation of TAM-induced tumor glycolysis by reparixin might exhibit an antitumor impact and offer a potential therapeutic target for PDAC.

Taken together, our study implicates CXCL1 as a critical role in ERBC growth and metastasis via crosstalk with fibroblast and cotargeting CXCR1/2 and CDK4/6 could potentially overcome endocrine resistant breast cancer.

In addition, our results demonstrate that IFN-α exposure significantly increases the differentiation of HCC stem cells, but this effect is reversed by the addition of the CXCL8 receptor CXCR1/2 inhibitor Reparixin and STAT3 inhibitor Stattic...Overall, our findings clarify that IFN-α triggers immunosuppression and cancer stem cell differentiation in hepatocellular carcinoma by upregulating CXCL8 secretion. This discovery provides a novel approach to enhance the effectiveness of HCC treatment in the future.

P1, N=20, Recruiting, University of Rochester | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Jan 2024 --> Jan 2025

Safety and tolerability of the combination were manageable. (Trial registration: ClinicalTrials.gov , NCT03473925).

P2, N=53, Not yet recruiting, Syntrix Biosystems, Inc.

P2, N=350, Recruiting, Eli Lilly and Company | Phase classification: P2b --> P2 | Trial completion date: Jul 2026 --> Mar 2026 | Trial primary completion date: Jul 2025 --> Apr 2025

SB225002 (a CXCR2 inhibitor) treatment significantly impairs SiHa cell-induced neutrophil migration...Conditioned medium of tumor-associated neutrophils (TANs) can drastically enhance cervical cancer cell growth in vitro and in vivo. The CXCLs-CXCR2 axis is critical in neutrophil recruitment and tumor cell proliferation in the cervical cancer microenvironment.

P1/2, N=53, Recruiting, M.D. Anderson Cancer Center | Trial completion date: Jan 2024 --> Jan 2025 | Trial primary completion date: Jan 2024 --> Jan 2025

P1/2, N=340, Active, not recruiting, AstraZeneca | Phase classification: P1b/2 --> P1/2 | Trial completion date: Dec 2023 --> Mar 2025

P2, N=26, Recruiting, Icahn School of Medicine at Mount Sinai

P1, N=77, Recruiting, Syntrix Biosystems, Inc. | Trial completion date: Dec 2023 --> Jun 2026 | Trial primary completion date: Jul 2023 --> Jun 2025

P1/2, N=50, Not yet recruiting, National Cancer Institute (NCI)

Targeting CAF-derived IL-8 may defeat PD-L1 upregulation-mediated immune resistance in GC cells, which provides a novel approach to improve the immunotherapeutic efficacies of patients with GC.

P2b, N=350, Recruiting, Eli Lilly and Company | Not yet recruiting --> Recruiting

P1, N=151, Recruiting, Syntrix Biosystems, Inc. | N=64 --> 151 | Trial completion date: Mar 2024 --> Mar 2029 | Trial primary completion date: Aug 2023 --> Mar 2028

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.