Arylsulfonamide 64B inhibits hypoxia/HIF-induced expression of c-Met and CXCR4 and reduces primary tumor growth and metastasis of uveal melanoma

Purpose: Uveal melanoma (UM) is the most prevalent and lethal intraocularmalignancy in adults. Here, we examined the importance of hypoxia in UM growth and tested the anti-tumor effects of arylsulfonamide 64B, an inhibitor of the hypoxia-induced factor (HIF) pathway in animal models of UM and investigated the related mechanisms. Experimental Design: UM cells were implanted in the uvea of mice eyes and mice systemically treated with 64B. Drug effect on primary eye tumor growth, circulating tumor cells, metastasis formation in liver and survival were examined. 64B effects on UM cell growth, invasion and hypoxia-induced expression of C-X-C chemokine receptor type 4 (CXCR4) and mesenchymal-epithelial transition factor (c-Met)were measured. Luciferase reporter assays, chromatin immunoprecipitation, co-immunoprecipitation and cellular thermal shift assays were used to determine how 64B interferes with the HIF transcriptional complex. Results: Systemic administration of 64B had potent anti-tumor effects against UM in several orthotopic mouse models, suppressing UM growth in the eye (~70% reduction) and spontaneous liver metastasis (~50% reduction), and extending mice survival (p< 0.001) while being well tolerated. 64B inhibited hypoxia-induced expression of CXCR4 and c-Met,two key drivers of tumor invasion and metastasis. 64B disrupted HIF-1 complex by interfering with HIF-1α binding to p300/CBP co-factors, reducing p300 recruitment to the METand CXCR4gene promoters. 64B could thermo-stabilize p300, supporting direct 64B binding to p300. Conclusions: Our pre-clinical efficacy studies support the further optimization of the 64B chemical scaffold towards a clinical candidate for the treatment of UM.

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