EUROSTARS E! 8155 – Nox4IS – Neuroprotective therapy for ischemic stroke

Participants: Maastricht University (MU, NL) and Glucox Biotech AB (GB, SE)  

The goal by GB is to identify and develop Nox4 inhibitors into pharmaceuticals that have satisfactory affinity, selectivity, potency, solubility, non-toxic (FTIA) and metabolic stability (PK). These inhibitors are then investigated in ischemic-stroke of animal models by UM.  The Nox4 inhibitors should then be capable in inhibiting Nox4 activity and prevent neuronal damage in ischemic-stroke of animal models.  

From the initial high throughput screen (HTS) hit substance GLX701313 demonstrated efficient target inhibition in cell-free membrane preparation and Nox4 selectivity. GLX701313 also showed efficacy in in vitro functionally assays stroke models, with cells such as Hippocampal Brain Slices (HBS) from rat and Human Microvascular Endothelial Cells (HMVEC) subjected to oxygen and glucose deprivation and reperfusion and also inhibiting Nox4-dependent TGFb-induced fibroblast differentiation into myofibroblasts.

Two Nox4 inhibitors demonstrating the highest selectivity to Nox4 inhibition in relation to other Nox-isoforms is presently the most important compounds in Glucox´ pipeline. These Nox4 inhibitors did successfully demonstrate neuroprotective effect in two different in vitro stroke models. Hippocampal Brain Slices that were subjected to oxygen and glucose deprivation (OGD) in an acute model and Human Brain Micro vascular Endothelial Cells (HBMEC) were subjected to hypoxia and starvation. Following hypoxia/starvation the cells were tested of its viability. These models has been very successful to determine in vivo efficacy of other less efficient substances, according to Glucox´ collaborators, headed by prof. Harald Schmidt, who performed the tests at Maastricht University (NL).  The two compounds are planned for in vivo tests in stroke induced animals at the fourth quarter of 2016.  

Principal Investigator: