Projects

Projects in Pipeline 

Glucox Biotech projects aim at developing novel small molecule inhibitors highly specific of  NAD(P)H-oxidase and to define type 2 diabetes patient groups that would particularly benefit from treatment with these inhibitors. 

SAR approach: Computer identified structure-activity relationships to known NAD(P)H-oxidase inhibitors has produced a set of novel inhibitory compounds. These have been found to lower blood glucose levels and improve insulin sensitivity in diabetic animals. Thus proof of principle has been obtained in accordance with convincing literature. 

HTS approach: High throughput screening of chemicals for NOX4 inhibition resulted in 700 hits that were funnelled down 20 promising compounds. The project is in hit-to-lead phase and selectivity against NOX2 has been established for a number of development compounds. 

In-licensing approach: A candidate drug (CD) has been inlicensed from Swedish Orphan Biovitrum. It is effective in decreasing food intake, body weight, blood glucose and insulin levels in animal models of obesity. It acts on both peripheral tissues and in CNS and it acts as an activator of the large conductance KATP channel. 

Identification of genetic markers: A project has been initiated for the identification of patient subpopulations genetically prone to increased sensitivity to reactive oxygen species and the development of screening procedures for identification of diabetes patients particularly benefitting from NOX4 inhibition. 


        




         The role of NAD(P)H-oxidase in different indications

Diabetes : In vivo experiments – in mouse and rat models - made by Glucox have indicate that NAD(P)H-oxidase inhibition improves glucose sensitivity. Literature support may be found in e. g.: Evans LE et al., 2003, Diabetes 52, 1-8, Wei Y et al., 2006 J Biol Chem 281, 35137-35146, Bloch K et al., 2009 PNAS 106, 14385-14390.

Nephropathy: Regarding the development of diabetic complication, the involvement of Nox4 in nephropathy, in podocytes response to high glucose concentrations is relevant: Sedeek M et al., Am J Physiol Renal Physiol. 2010 Dec; 299(6);  Eid AA et al., J Biol Chem. 2010 Nov 26; 285(48). 

Heart: The connection of NOX4 in mitochondrial dysfunction in “the aging heart” is very interesting (Tetsuro Ago et al., AGING, December 2010, vol.2 No 12). The review Maejima Y et al., 2011 “Regulation of myocardial growth and death by NADPH oxidase” point to NOX4 as a candidate for myocardial cell death also”NADPH oxidase 4 is a major source of oxidative stress in the failing heart” Kuroda J et al., PNAS USA 2010 Aug 31; 107.

Endothelial dysfunction is a crucial step in the pathogenesis of cardiovascular diseases and diabetes. There is a strong connection of NADPH oxidase and dysfunctional endothelial cells – “Activation of NF-kappaB by palmitate in endothelial cells: a key role for NADPH oxidase-derived superoxide in response to TLR4 activation (NOX4 knockdown by siRNA)” Maloney E et al., Arterioscler Throm Vasc Biol. 2009 sep;29(9). Thus – the implication of the connection of fatty acids and cellular inflammation.

Neuropathy: NOX4-dependent H2O2 production contributes to glutamate toxicity in primary cortical neurons, Ha JS et al., Exp Cell Res. 2010 Jun 10; 316(10)

 



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