U-104

U-104 is a novel ureido-sulfonamide inhibitor of Carbonic Anhydrase IX (CAIX). Tumor volume measurements show important inhibition of primary tumor growth in the mice treated with the U-104 compound compared with vehicle controls. It also has ability to inhibit metastasis formation in the 4T1 experimental metastasis model.

Reference

Yuanmei Lou, Paul C. McDonald, Arusha Oloumi, Stephen Chia, Christina Ostlund, Ardalan Ahmadi, Alastair Kyle, Ulrich auf dem Keller, Samuel Leung, David Huntsman, Blaise Clarke, Brent W. Sutherland, Dawn Waterhouse, Marcel Bally, Calvin Roskelley, Christopher M. Overall, Andrew Minchinton, Fabio Pacchiano, Fabrizio Carta, Andrea Scozzafava, Nadia Touisni, Jean-Yves Winum, Claudiu T. Supuran, Shoukat Dedhar. Targeting Tumor Hypoxia: Suppression of Breast Tumor Growth and Metastasis by Novel Carbonic Anhydrase IX Inhibitors. Cancer Research May 1, 2011 71; 3364

Activation of carbonic anhydrase IX by alternatively spliced tissue factor under late-stage tumor conditions.[Pubmed:27721473]

Lab Invest. 2016 Dec;96(12):1234-1245.

Molecules of the coagulation pathway predispose patients to cancer-associated thrombosis and also trigger intracellular signaling pathways that promote cancer progression. The primary transcript of tissue factor, the main physiologic trigger of blood clotting, can undergo alternative splicing yielding a secreted variant, termed asTF (alternatively spliced tissue factor). asTF is not required for normal hemostasis, but its expression levels positively correlate with advanced tumor stages in several cancers, including pancreatic adenocarcinoma. The asTF-overexpressing pancreatic ductal adenocarcinoma cell line Pt45.P1/asTF+ and its parent cell line Pt45.P1 were tested for growth and mobility under normoxic conditions that model early-stage tumors, and in the hypoxic environment of late-stage cancers. asTF overexpression in Pt45.P1 cells conveys increased proliferative ability. According to cell cycle analysis, the major fraction of Pt45.P1/asTF+ cells reside in the dividing G2/M phase of the cell cycle, whereas the parental Pt45.P1 cells are mostly confined to the quiescent G0/G1 phase. asTF overexpression is also associated with significantly higher mobility in cells plated under either normoxia or hypoxia. A hypoxic environment leads to upregulation of carbonic anhydrase IX (CAIX), which is more pronounced in Pt45.P1/asTF+ cells. Inhibition of CAIX by the compound U-104 significantly decreases cell growth and mobility of Pt45.P1/asTF+ cells in hypoxia, but not in normoxia. U-104 also reduces the growth of Pt45.P1/asTF+ orthotopic tumors in nude mice. CAIX is a novel downstream mediator of asTF in pancreatic cancer, particularly under hypoxic conditions that model late-stage tumor microenvironment.

Synthesis and evaluation of 18F-labeled carbonic anhydrase IX inhibitors for imaging with positron emission tomography.[Pubmed:23463940]

J Enzyme Inhib Med Chem. 2014 Apr;29(2):249-55.

Two carbonic anhydrase IX (CA IX) inhibitors were radiolabeled with (18)F, and evaluated for imaging CA IX expression. Despite good affinity for CA IX and excellent plasma stability, uptake of both tracers in CA IX-expressing HT-29 tumor xenografts in mice was low. (18)F-FEC accumulated predominately in the liver and nasal cavity, whereas a significant amount of (18)F-U-104 was retained in blood. Due to minimal uptake in HT-29 tumors compared to other organs/tissues, these two tracers are not suitable for use for CA IX-targeted imaging.

Blood lipid abnormality changes the rate of alveolar-capillary uptake of sevoflurane: a prospective, non-interventional, clinical study.[Pubmed:27719742]

Int J Clin Pharmacol Ther. 2017 Feb;55(2):156-162.

OBJECTIVE: This research studied the influence of different blood lipid components on the rate of alveolar-capillary uptake of sevoflurane. Method: 104 patients aged 20 - 50 years undergoing elective operations under general anesthesia were mechanically ventilated through endotracheal intubation after intravenous injections of midazolam, vecuronium, fentanyl, and etomidate. They inhaled 2% sevoflurane at an oxygen flow of 2 L/min, then the inspired concentrations (F_I) and expired concentrations (F_A of sevoflurane were recorded at 1, 3, 5, 7, 10, 15, 20, and 30 minutes. These cases were divided into a normal group and an abnormal group according to the lipid levels. Then, based on the lipid criteria, those cases with abnormal lipid levels were classified into a high-triglyceride (TG) and total-cholesterol (TC) group (group TG+TC) and a group with decreased high-density lipoprotein cholesterol (group HDL-C).The values of F_A/F_I and the times required to reach the titration value F_A/F_I = 0.8 were calculated were calculated for each group. RESULTS: Compared with the normal group, F_A/F_I decreased within 7 - 10 minutes (p < 0.05) and the time taken to reach the titration value was prolonged in the abnormal group (p < 0.05). The value of F_A/F_I decreased during 7 - 10 minutes (p < 0.05) and the time taken to reach the titration value was longer (p < 0.05) in the group TG+TC. CONCLUSIONS: The increased value of blood/gas partition coefficients (B/G) was caused by the increase in the concentrations of TG and TC in blood lipids..

Influence of amplitude-related perfusion parameters in the parotid glands by non-fat-saturated dynamic contrast-enhanced magnetic resonance imaging.[Pubmed:27036583]

Med Phys. 2016 Apr;43(4):1873.

PURPOSE: To verify whether quantification of parotid perfusion is affected by fat signals on non-fat-saturated (NFS) dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and whether the influence of fat is reduced with fat saturation (FS). METHODS: This study consisted of three parts. First, a retrospective study analyzed DCE-MRI data previously acquired on different patients using NFS (n = 18) or FS (n = 18) scans. Second, a phantom study simulated the signal enhancements in the presence of gadolinium contrast agent at six concentrations and three fat contents. Finally, a prospective study recruited nine healthy volunteers to investigate the influence of fat suppression on perfusion quantification on the same subjects. Parotid perfusion parameters were derived from NFS and FS DCE-MRI data using both pharmacokinetic model analysis and semiquantitative parametric analysis. T tests and linear regression analysis were used for statistical analysis with correction for multiple comparisons. RESULTS: NFS scans showed lower amplitude-related parameters, including parameter A, peak enhancement (PE), and slope than FS scans in the patients (all with P < 0.0167). The relative signal enhancement in the phantoms was proportional to the dose of contrast agent and was lower in NFS scans than in FS scans. The volunteer study showed lower parameter A (6.75 +/- 2.38 a.u.), PE (42.12% +/- 14.87%), and slope (1.43% +/- 0.54% s(-1)) in NFS scans as compared to 17.63 +/- 8.56 a.u., 104.22% +/- 25.15%, and 9.68% +/- 1.67% s(-1), respectively, in FS scans (all with P < 0.005). These amplitude-related parameters were negatively associated with the fat content in NFS scans only (all with P < 0.05). CONCLUSIONS: On NFS DCE-MRI, quantification of parotid perfusion is adversely affected by the presence of fat signals for all amplitude-related parameters. The influence could be reduced on FS scans.

Targeting carbonic anhydrase IX depletes breast cancer stem cells within the hypoxic niche.[Pubmed:23208505]

Oncogene. 2013 Oct 31;32(44):5210-9.

The sub-population of tumor cells termed 'cancer stem cells' (CSCs) possess the capability to generate tumors, undergo epithelial-mesenchymal transition (EMT) and are implicated in metastasis, making treatments to specifically target CSCs an attractive therapeutic strategy. Tumor hypoxia plays a key role in regulating EMT and cancer stem cell function. Carbonic anhydrase IX (CAIX) is a hypoxia-inducible protein that regulates cellular pH to promote cancer cell survival and invasion in hypoxic microenvironments and is a biomarker of poor prognosis for breast cancer metastasis and survival. Here, we demonstrate that inhibition of CAIX expression or activity with novel small-molecule inhibitors in breast cancer cell lines, or in primary metastatic breast cancer cells, results in the inhibition of breast CSC expansion in hypoxia. We identify the mTORC1 axis as a critical pathway downstream of CAIX in the regulation of cancer stem cell function. CAIX is also required for expression of EMT markers and regulators, as well as drivers of 'stemness', such as Notch1 and Jagged1 in isolated CSCs. In addition, treatment of mice bearing orthotopic breast tumors with CAIX-specific small-molecule inhibitors results in significant depletion of CSCs within these tumors. Furthermore, combination treatment with paclitaxel results in enhanced tumor growth delay and eradication of lung metastases. These data demonstrate that CAIX is a critical mediator of the expansion of breast CSCs in hypoxic niches by sustaining the mesenchymal and 'stemness' phenotypes of these cells, making CAIX an important therapeutic target for selectively depleting breast CSCs.

Targeting tumor hypoxia: suppression of breast tumor growth and metastasis by novel carbonic anhydrase IX inhibitors.[Pubmed:21415165]

Cancer Res. 2011 May 1;71(9):3364-76.

Carbonic anhydrase IX (CAIX) is a hypoxia and HIF-1-inducible protein that regulates intra- and extracellular pH under hypoxic conditions and promotes tumor cell survival and invasion in hypoxic microenvironments. Interrogation of 3,630 human breast cancers provided definitive evidence of CAIX as an independent poor prognostic biomarker for distant metastases and survival. shRNA-mediated depletion of CAIX expression in 4T1 mouse metastatic breast cancer cells capable of inducing CAIX in hypoxia resulted in regression of orthotopic mammary tumors and inhibition of spontaneous lung metastasis formation. Stable depletion of CAIX in MDA-MB-231 human breast cancer xenografts also resulted in attenuation of primary tumor growth. CAIX depletion in the 4T1 cells led to caspase-independent cell death and reversal of extracellular acidosis under hypoxic conditions in vitro. Treatment of mice harboring CAIX-positive 4T1 mammary tumors with novel CAIX-specific small molecule inhibitors that mimicked the effects of CAIX depletion in vitro resulted in significant inhibition of tumor growth and metastasis formation in both spontaneous and experimental models of metastasis, without inhibitory effects on CAIX-negative tumors. Similar inhibitory effects on primary tumor growth were observed in mice harboring orthotopic tumors comprised of lung metatstatic MDA-MB-231 LM2-4(Luc+) cells. Our findings show that CAIX is vital for growth and metastasis of hypoxic breast tumors and is a specific, targetable biomarker for breast cancer metastasis.

U-104 is a potent carbonic anhydrase (CA) inhibitor for CA IX and CA XII with Ki of 45.1 nM and 4.5 nM; low inhibition for CA I and CA II.

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