NOX66 is a suppository formulation of the experimental drug, idronoxil.
IDRONOXIL – Heritage
Idronoxil is an analogue of the plant hormone, genistein.
Genistein was identified in the 1990s as a promising anti-cancer drug because of its ability to inhibit a ubiquitous family of human enzymes known as protein kinases. There are some hundreds of different protein kinases in a cell, accounting for one of the largest family of enzymes in the body.
Kinases don’t participate directly in a particular end-function….their function is to activate the various other proteins that themselves are responsible for carrying out the particular function.
A protein kinase activates other proteins by chemically adding a phosphate group to them in a process known as phosphorylation. The phosphate is sourced from adenosine tri-phosphate (ATP), a ubiquitous compound within the body that is the source of much of the body’s energy. The ATP is the electricity and the kinase the electrical cord delivering the electricity to the appliance.
The protein kinases are sub-grouped according to the type of amino acids on the receptor protein to which the phosphate group is attached. Tyrosineand serine/threonine are the three principal amino acid residues involved, thus the kinases generally are classified as tyrosine kinases or serine-threonine kinases.
Genistein is an inhibitor predominantly of the tyrosine kinases, with some activity against serine/threonine kinases. Genistein remains the most effective known inhibitor of tyrosine kinases, inhibiting almost the full range of known human tyrosine kinases. The therapeutic significance of this lies in the fact that a number of key kinases are over-expressed in diseased states such as cancer, driving many of the out-of-control behaviours associated with cancer including excessive growth, undifferentiation, development of drug-resistance mechanisms, unresponsiveness to normal control mechanisms, and perpetual survival.
Genistein, however, is not sufficiently drug-like to be considered as an anti-cancer therapeutic in its own right….. it’s anti-cancer action are modest at best, plus it is extensively metabolised in the body to inactive compounds.
Idronoxil is a structural analogue of genistein, selected for its greater potency and not being susceptible to Phase 1 metabolism.
IDRONOXIL – Mechanism of action
Idronoxil, like genistein, is pleiotropic, meaning that it hits multiple targets, tyrosine kinases being just one target.
Sphingosine kinase. This tyrosine kinase is considered a key target of idronoxil and idronoxil can be considered a first-in-class sphingosine kinase inhibitor in cancer cells specifically. Sphingosine kinase is a key upstream regulator of most of a cell’s pro-survival functions. It is the major component of the rheostat within a cell’s outer membrane that switches a cell’s signalling functions from death to survival. Inhibition of sphingosine kinase blocks the production of sphingosine-1-phosphate, resulting in loss of activity of downstream enzymes such as PI3 kinase, in turn blocking phosphorylation of key switches such as Akt/mTOR and enzymes involved in DNA repair and stabilisation such as PARP 1 and topoisomerases 1 and 2.
ENOX2. External membrane NADH oxidase Type 2 also is inhibited directly, highlighting the pleiotropy of this compound additional to its kinase-inhibiting actions. NADH oxidases regulate the transmembrane electron potential (TMEP) across cell membranes by the battery-like transfer of protons (H+) across membranes, that potential then providing the energy source for the diverse functions of membranes. ENOX enzymes regulate the movement of protons across the cell’s external membrane, with human DNA capable of making two ENOX isoforms. ENOX1 is the normal, constitutive form, but is replaced on cancer cells by its splice variant, ENOX2. ENOX2 also displays characteristics of a prion. Inhibition of ENOX2 leads to a loss of TMEP in the plasma membrane, depriving the membrane of its primary energy source; the build-up of protons in the membrane also indirectly inhibits the activity of sphingosine kinase.
Biological effects. The combined direct and indirect inhibitory effects on sphingosine kinase activity lead to withdrawal of pro-survival signalling (sphingosine-1-phosphate) and activation of pro-death signalling (ceramide).
Idronoxil has no known adverse effects on healthy cells. This absence of any toxicity against healthy cells is explained in terms of its ENOX2 target which is not expressed on healthy cells. But in the case of tyrosine kinase targets such as sphingosine kinase, the answer is less clear, given that there is no known structural or functional difference between a kinase behaving normally in a healthy cell and the same kinase being expressed at a higher level in a cancer cell. The selectivity of idronoxil in having no inhibitory effect on kinase activity in healthy cells points to the existence of such a difference, opening a potentially major new area of medical research.
IDRONOXIL – Indications
Idronoxil displays anti-cancer activity against all forms of cancer tested in vitro and in vivo to date, using cells representative of all major forms of cancer.
While having a modest ability to kill cancer cells(IC50 range between about 1-5 uM), pre-clinical studies point to its optimal use beingto sensitise cancer cells to the toxic effects of standard therapies (chemotherapy and radiotherapy). The rationale is that a sub-lethal inhibitory effect on sphingosine kinase activity reduces the ability of the cancer cell to operate drug-resistance mechanisms and to effect repair of drug- or radiation-induced damage to DNA. In the case of cytotoxic drugs such as cisplatin, carboplatin, paclitaxel, doxorubicin and gemcitabine, idronoxil is an exquisite sensitiser, increasing the cytotoxic potential of those agents by between 103 -105 times, in the process restoring sensitivity to cancer cells highly refractory to those agents.
IDRONOXIL – NOX66
A succession of clinical trials (between 1999–2009) involving over 400 patients with late-stage cancer revealed evidence of clinical benefit both as a monotherapy and in combination therapy with carboplatin or paclitaxel. However, that benefit was too inconsistent to warrant further development of the drug.
Noxopharm believes that this failure stems from the susceptibility of idronoxil to Phase 2 metabolism, with virtually 100% conversion of this water-insoluble drug to a water-soluble conjugate with glucuronic acid. Phase 2 drug conjugates (eg. codeine, morphine, paracetamol, aspirin) circulating in blood are biologically inactive, but on entering cells are deconjugated to their active drug form. Phase 2 conjugation of idronoxil similarly leads to its inactivation, but in common with other drugs treated in this similar way, was not considered a block to its ability to work.
That belief has now been shown to be misplaced, with cancer cells now understood to lack the ability to reactivate the drug as healthy cells are able to do. This loss of activity being another part of a cancer cell’s development of resistance mechanisms.
NOX66 has been designed to overcome this problem. Presenting idronoxil to the body in the form of NOX66 leads to the drug being present in the blood in a complexed form known as idronoxil-C. At the very least, idronoxil-C achieves the primary aim of protecting the drug from being metabolised and thereby avoiding inactivation. But idronoxil-C goes beyond this benefit, endowing idronoxil with far more valuable drug-like properties such as keeping the drug circulating in the blood for a considerably longer time than the native form of idronoxil.