Noxopharm White Paper

3 Disclaimer: Veyonda is currently not approved in Australia or any other country Inhibits ENOX2 Human cells rely on two types of ENOX enzymes: ENOX1 and ENOX2 . • Majority of normal adult cells express ENOX1 only. • Cells with high rates of turnover (eg. hematopoietic, myeloid, gut mucosal cells express mainly ENOX1 and some ENOX2. • Cancer cells only express ENOX2 and all forms of cancer appear to express only ENOX2. ENOX1 and ENOX2 differ in their oscillation times: 24 and 22 minutes respectively. The shorter oscillation time of ENOX2 is associated with faster cell division and need for higher rate of cell growth, with that need initiating the preferential expression of ENOX2 . Idronoxil only binds to and inhibits ENOX2. Shutting down ENOX2 function blocks the movement of atomic particles across the cell membrane, leading to the accumulation of protons (H+) in the form of CoQ 10 H. High levels of CoQ 10 H inhibit the enzyme, sphingosine kinase 1 (SphK1) . SphK1 plays a pivotal role in the sphingomyelin pathway in the plasma membrane, converting ceramide into sphingosine-1-phosphate (S1P) . Ceramide and S1P are critically important secondary messengers, determining whether a cell lives (S1P) or dies (ceramide) . Most cancers express high levels of SphK1 activity, resulting in very high levels of S1P. Inhibits sphingosine kinase 1 Pro-death signaling • Apoptosis • Mitotic arrest • Anti-angiogenesis Pro-life signaling • Inhibit apoptosis • Cell migration • Angiogenesis • Immune cell activation • Immune cell trafficking Ceramide Sphingosine kinase 1 death survival Sphingosine-1 -phosphate SphK1 Sphingosine-1-phosphate (S1P) delivers its pro-survival effects by exiting the cell where it interacts with 5 S1P receptors located on the outer surface of the cell (called S1PR1-5). Each S1P receptor then activates a range of pro-survival signaling pathways, in a highly complex cross-promotional manner. By inhibiting SphK1 , levels of S1P in turn drop, preventing activation of these critical survival pathways and depriving the cancer cell of its pro-survival advantages. In this way, the inhibitory effect of idronoxil is restricted very largely to cancer cells. Inhibits sphingosine-1-phosphate S1PR1 (EDG1) S1PR5 (EDG8) S1PR4 (EDG6) S1PR3 (EDG3) CELLULAR RESPONSE S1PR2 (EDG5) JNK Rho PI3K PLC AC ERK ERK Gi Gi Gi Gi Gi Gq Gq G 12 G 12 G 12 G 13 S1P Time Keeping Function Protein substrates Plasma membrane electron transport ECTO-NOX protein PROTEIN DISFULFIDE-THIOL INTERCHANGE 11 min QUINOL (NAD(P)H) OXIDATION 11 min