navarixin (MK-7123)

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.