**Background**
Tumor hypoxia is a hallmark of solid tumors, often leading to the overexpression of specific enzymes that regulate pH balance to support cancer cell survival and progression. Carbonic anhydrases (CAs), particularly CA IX and CA XII, are transmembrane enzymes that are frequently upregulated in hypoxic tumor environments. These enzymes catalyze the reversible hydration of carbon dioxide, contributing to an acidic extracellular pH that promotes tumor invasion, metastasis, and resistance to therapy. Consequently, targeting these isoforms has become a significant strategy in oncology to disrupt the hypoxic niche and deplete cancer stem cell populations. In this context, we will introduce a potent inhibitor of CA IX and CA XII – U-104.
**Definition**
U-104 (also known as SLC-0111) is a potent carbonic anhydrase inhibitor with high selectivity for CA IX (Ki = 45.1 nM) and CA XII (Ki = 4.5 nM), while exhibiting low inhibition for CA I (Ki = 5080 nM) and CA II (Ki = 9640 nM).
**In Vitro and In Vivo Studies**
The U-104 description highlights its versatility as both a CA inhibitor and a potent exosome inhibitor. In terms of U-104 biological activity in vitro, treatment with 50 μM U-104 for 72 hours blocks the mesenchymal phenotype in cancer stem cell populations within hypoxic 4T1 cells. Furthermore, concentrations below 50 μM significantly reduce migration in a dose-dependent manner in metastatic MDA-MB-231 LM2-4 Luc+ cells. Antiproliferative assays have shown that U-104 exhibits IC50 values of 18.22 μM to 138 μM against MDA-MB-231 cells and 58 μM against U-87MG cells under hypoxic conditions.
U-104 in vivo studies have demonstrated significant antitumor efficacy across various models. In mice implanted orthotopically with MDA-MB-231 LM2-4 Luc+ cells, daily administration of 19 or 38 mg/kg for 27 days inhibited primary tumor growth. Specifically, 38 mg/kg administered i.p. from day 11 to 27 significantly delayed tumor growth and reduced the cancer stem cell population in NOD/SCID mice. Additionally, U-104 (19 mg/kg daily for 5 days) inhibited metastasis formation in 4T1 experimental models, while oral gavage (50 mg/kg, 4 days on/1 day off) significantly delayed tumor growth in Balb/c mice implanted with 4T1 cells. In conclusion, U-104 is a potent and selective CA IX/XII inhibitor that effectively suppresses tumor growth and metastasis in U-104 cancer research.
Keywords
U-104, 178606-66-1, SLC-0111, U104, U 104, SLC0111, SLC 0111, Carbonic Anhydrase, Carbonate dehydratase, CAIX, CAXII, exosome, CAI, CAII, 4T1
References
[1] Lou Y, et al. Targeting tumor hypoxia: suppression of breast tumor growth and metastasis by novel carbonic anhydrase IX inhibitors. Cancer Res. 2011 May 1;71(9):3364-76.
[2] Lock FE, et al. Targeting carbonic anhydrase IX depletes breast cancer stem cells within the hypoxic niche. Oncogene. 2013 Oct 31;32(44):5210-9.
[3] Huarui Zhang, et al. Advances in the discovery of exosome inhibitors in cancer. J Enzyme Inhib Med Chem. 2020 Dec;35(1):1322-1330.