14 research outputs found
Novel Pyridazinone Inhibitors for Vascular Adhesion Proteinâ1 (VAP-1): Old TargetâNew Inhibition Mode
Vascular
adhesion protein-1 (VAP-1) is a primary amine oxidase and a drug target
for inflammatory and vascular diseases. Despite extensive attempts
to develop potent, specific, and reversible inhibitors of its enzyme
activity, the task has proven challenging. Here we report the synthesis,
inhibitory activity, and molecular binding mode of novel pyridazinone
inhibitors, which show specificity for VAP-1 over monoamine and diamine
oxidases. The crystal structures of three inhibitorâVAP-1 complexes
show that these compounds bind reversibly into a unique binding site
in the active site channel. Although they are good inhibitors of human
VAP-1, they do not inhibit rodent VAP-1 well. To investigate this
further, we used homology modeling and structural comparison to identify
amino acid differences, which explain the species-specific binding
properties. Our results prove the potency and specificity of these
new inhibitors, and the detailed characterization of their binding
mode is of importance for further development of VAP-1 inhibitors
Heparin-like polysaccharides reduce osteolytic bone destruction and tumor growth in a mouse model of breast cancer bone metastasis
Abstract
Transforming growth factor ÎČ (TGF-ÎČ) is a key regulator of several steps in cancer metastasis, including the establishment of bone metastatic lesions. TGF-ÎČ is released from bone during osteoclastic bone resorption and it stimulates breast cancer cells to produce osteolytic factors such as interleukin 11 (IL-11). We conducted a cell-based siRNA screen and identified heparan sulfate 6-O-sulfotransferase 2 (HS6ST2) as a critical gene for TGF-ÎČ-induced IL-11 production in highly bone metastatic MDA-MB-231(SA) breast cancer cells. HS6ST2 attaches sulfate groups to glucosamine residues in heparin sulfate which is a member of the glycosaminoglycan family of carbohydrates. Our subsequent studies with highly sulfated heparin-like glycosaminoglycans (HLGAGs) with low anti-coagulant activity indicated that a high-molecular-weight E. coli K5-derived heparin-like polysaccharide (K5-NSOS) inhibited TGF-ÎČ-induced IL-11 production in MDA-MB-231(SA) cells. We then evaluated the therapeutic potential of K5-NSOS and a low-molecular-weight synthetic heparin (fragmin) in a mouse model of breast cancer bone metastasis. MDA-MB-231(SA) cells were inoculated into the left cardiac ventricle of athymic nude mice which were then administered with K5-NSOS, fragmin, or vehicle once daily for 4 weeks. Both HLGAGs increased body weight, decreased osteolytic lesion area, and reduced tumor burden in bone. Our in vitro studies showed that both K5-NSOS and fragmin inhibited adhesion of breast cancer cells to ICAM-1, and K5-NSOS also inhibited adhesion to E- and P-selectin. Furthermore, K5-NSOS inhibited bone resorption activity of human osteoclasts in vitro. Our data support and further clarify the critical role of heparan sulfate glycosaminoglycans in breast cancer metastasis and indicate that K5-NSOS is a potential antimetastatic and antiresorptive agent with low anticoagulant activity that could be further optimized as an anti-tumor agent.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 845. doi:10.1158/1538-7445.AM2011-845</jats:p