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The neuroblastoma cells produce carbonic anhydrase IX (CA IX), an enzyme crucial for the survival of cancer cells in low\u2010oxygen environments.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>We designed and synthesised a novel high\u2010affinity inhibitor of CA IX. The highest to\u2010date. The affinities were determined for all human catalytically active CA isozymes showing significant selectivity for CA IX over other isozymes. The inhibitor effect on neuroblastoma cancer cell growth was determined <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic> via a mice xenograft model.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>The novel designed inhibitor effectively mitigated the acidification induced by CA IX and reduced spheroid growth under hypoxic conditions in the SK\u2010N\u2010AS cell line. It also diminished the secretion of pro\u2010tumour chemokines IL\u20108 (CXCL2) and CCL2. When we combined this novel CA IX inhibitor with a compound that inhibits the chemokine receptor CCR2 protein activity, we observed a reduction in mouse tumour growth. The combined treatment also prompted tumours to exhibit adaptive resistance by producing higher levels of vascular endothelial growth factor receptors (VEGFR) and other compensatory signals.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Implications<\/jats:title><jats:p>This research underscores the pivotal role of CA IX in cancer and the potential of a novel CA IX inhibitor\u2010based combination intervention therapy for neuroblastoma treatment.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.17429","type":"journal-article","created":{"date-parts":[[2025,1,8]],"date-time":"2025-01-08T05:44:09Z","timestamp":1736315049000},"page":"1610-1629","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Carbonic anhydrase IX inhibition as a path to treat neuroblastoma"],"prefix":"10.1111","volume":"182","author":[{"given":"Agne","family":"Petrosiute","sequence":"first","affiliation":[{"name":"Department of 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