The Eurostar supported project ”Neuroprotective therapy for ischemic stroke” a collaboration between Glucox Biotech AB (GB) and prof. Harald Schmidt at Maastricht University (UM) is approaching its finalization.
Early restoration of cerebral blood is essential to minimize brain damage that will occur in an ischemic stroke event. The paradox that more damage occurs at the return of the blood flow is well known. Prof. Harald Schmidt has previously demonstrated the importance of enhanced NADPHoxidase 4 (Nox4) activity, in this pathological event, generating reactive oxygen which aggravates tissue damage and brain damage.
Thus a pharmaceutical that efficiently and selective inhibits Nox4 over activity is a hot candidate to minimize the brain damage that will occur in an ischemic stroke.
From GBs portfolio of Nox4 inhibitors four structurally different hits GLX481304, GLX351322, GLX351320, GLX701313 has been developed in a SAR medicinal program (GB) and tested in in vitro/in vivo-stroke models (UM).
The two SAR developed Nox4 inhibitors GLX7013114 and GLX7013107 originating from the hit GLX701313 demonstrate the highest selectivity to Nox4 inhibition in relation to other Nox-isoforms and are presently the most important Nox4 inhibitors in this project. These inhibitors demonstrate neuroprotective effect in two different in vitro stroke models at UM:”Hippocampal Brain Slices” (HBS) and ”Human Brain Micro vascular Endothelial Cells” (HBMEC) that were subjected to oxygen and glucose deprivation. FTIA without adverse effects and PK results provided the foundation of on-going in vivo study in mice stroke models.
The table show efficiency of the inhibitory action and selectivity in whole cell-assays expressing Nox-isoforms, and also the lack of ability to inhibit Xanthine Oxidase (XO). No endogenous redox activity of the two compounds was detected.
||Nox4 IC50 mM
|Endogenous redox activity
Glucox Biotech has success in Eurostars grant application and receives financing for compound development and stroke investigation in joint project with Maastricht University.
As a result of a successful application to the EU program Eurostars, Vinnova has grated Glucox Biotech financing for the project Neuroprotective Therapy for Ischemic Stroke. At the same time the Dutch authorities has granted Prof. Schmidt at Maastricht University funds for his part of the project.
Through collaboration with Maastricht University we aim to further develop our Nox4 inhibitors, including lead optimization, pharmacokinetics, ADMET, formulation development, proof of principle in animal studies and preclinical toxicology.
Recently, the group of Prof. Schmidt at Maastricht provided proof of concept that NOX4 represents a highly promising novel, mechanism-based therapeutic target for ischemic stroke. They showed that deletion of NOX4 in mice, but not of NOX1 or NOX2, not only massively reduces infarct sizes upon ischemic strokes, but also results in better neurological outcomes, protection of the blood-brain barrier, and improved survival.
As deletion of NOX4 in mice does not result in any apparent basic phenotype, its acute inhibition in humans after ischemic strokes is likely a safe therapy. Moreover, treatment of stroke patients with NOX4 inhibitors should not increase the risk of bleedings in case of a haemorrhagic stroke, as it is currently the case for the approved drug. Thus, the treatment could be started without the need for a CT scan.
Glucox Biotech has signed an agreement with Prof. Harald Schmidt of Maastricht University for further development of Glucox´ lead compound for treatment of ischemic stroke.
It has recently been shown that NOX4 is an effective therapeutic target in acute stroke. Prof. Harald Schmidt and his team have convincingly shown that significant increase in NOX4 activity is a main component in neuronal cell death that occurs in ischemic stroke. Within the collaboration Prof. Schmidt and co-workers will evaluate Glucox’ NOX4 inhibitors for further development into pharmaceuticals that will prevent neuronal cell death in ischemic stroke.
Ref: Radermacher, K., A., et al (2012) Experimental & Translational Stroke Medicine, 4:11 doi: 10.1186/2040-7378-4-11
Glucox Biotech has signed an agreement with Accelera Srl, Milano, Italy. Accelera will evaluate pharmacokinetics and time course of brain uptake of Glucox’ lead compounds in mice.
Two of Glucox’ NOX4 small molecule inhibitors have been shown to protect brain from nerve cell damage in a situation of induced acute ischemic stroke. To further elucidate the positive action of these compounds, time course of brain uptake will be investigated and evaluated.
Uppsala University and SLU have together with the European Regional Development Fund alloted Glucox Biotech and Professor Nils Welsh a SMURF grant for further studies of the protective action of Glucox´ lead compounds on beta cells.
In a pilot study one of Glucox´ proprietary specific Nox4 inhibitor compounds was found to protect beta cells in isolated pancreatic islets from high glucose induced cell death. The grant will be used to verify and elucidate the significance of this first observation. The project involves experiments in several different models.
Glucox Biotech has signed an agreement with Prof. Anders Arner of Karolinska Institutet for further testing of Glucox smal molecule NOX4 inhibitors in diabetic models.
Prof. Arner, Department of Physiology and Pharmacology, Division of Genetic Physiology, Karolinska Institutet, Stockholm has agreed to investigate the influence of several of Glucox’ proprietary compounds on parameters relevant to metabolic diseases in diabetic models.
Ref: Samocha-Bonet, D., et al (2009) Trends in Endocrinology and Metabolism, 21 (2), 83-88
Wu and coworkers undertook characterization of pathway-selective insulin resistance and responsivenes in liver and hepatocytes by examining targets of the insulin receptor including NOX4 pathways. They comcluded that functional disturbance of a single molecule, NAD(P)H oxidase 4, is sufficient to induce the key harmful features of deranged insulin signaling in type 2 diabetes mellitus, obesity, and other conditions associated with hyperinsulinemia and pathway-selective insulin resistance and responsiveness.
Ref: Wu, X., et al (2012) Arterioscler Thromb Vasc Biol. 2012 Feb 9. (Epubl ahead of print)
The mission of Glucox Botech is to identify compounds that improve glucose homeostasis. Together with two acadmic groups at Karolinska Institutet and Stockholm University, Glucox Biotech has shown that shikonin, a naphthoquinone derived from the Cinese plant Lithospermum erythrorhizon, increases glucose uptake i skeletal muscle cells.
Shikonin increases uptake via an insulin-independent, calcium dependent, pathway. The beneficial effects of shikonin on glucose metabolism, both in vitro and in vivo, show that the compound possesses properties that make it of considerable interest for developing novel treatments of type 2 diabetes.
Ref: Öberg, A.I., et al (2011) PLoS One, 6 (7): e22510
Glucox Biotech announceed today the signing of a contract with Redoxis AB for further studie on Glucox smal molecule NOX4 inhibitors.
Glucox Biotech owns several patents covering the exclusive rights to develop pharmaceutical substances for treating insulin resistance and diabetes on the basis of reducing reactive oxygen species produces by NAD(P)H-oxidase. Redoxis AB is a research company with focused research on autoimmune diseases and with a recognized competence in R&D related to NAD(P)H-oxidase based disease mechanisms. According to the contract Redoxis undertakes to, on a fee-for-service basis, further study the influence of Glucox´ small molecule NOX4 inhibitors on NAD(P)H-oxidase.
Erik Walum, former Chair of the Board of Directors was today appointed new CEO of Glucox Biotech AB. Mona Wilcke, co-founder of Glucox Biotech and former CEO, was at the same time appointed new Chair of the Board of Directors.
Erik Walum (PhD) is a former professor of Neurotoxicology at Stockholm University and has served as Head of Molecular Biology and Genomics at Pharmacia and Head of Obesity Pharmacology at Biovitrum. He became member of the Board in 2006 and Chair of the board in 2008.
Mona Wilcke (PhD) has a broad experience in business development as well as research in the metabolic and diabetes field. She has been working at several biotech and large pharmaceutical companies, among them Pharmacia. Besides being Chair of the Board of Directors she will also serves as CSO. Mona Wilcke has been a member of the Board since the start of the company in 2004.