From Chile via WEHI: new MS drug candidate

Researchers at the Walter and Eliza Hall Medical Research Australian and the University of California have developed one of the hottest prospective drug therapies for the paralysing neurodegenerative disorder multiple sclerosis (MS).

They have developed synthetic form of khellinone, a compound found in a Chilean relative of carrots, celery and hemlock.

The khellinone story begins in the 1960s with a Chilean rancher's efforts to find a natural remedy for his slow paralysis. Four decades on, his risky foray into self-medication may be about to bear golden fruit, in the form of a highly selective drug prospect for MS.

The rancher made herbal tea from the leaves of the Chilean ruta plant (Ammi visnaga), in the Apiaceae family. Slowly, his symptoms slowly resolved, to the point where he resumed riding his horse around his hacienda. In the 1980s researchers in Prof Wolfram Haensel's natural products chemistry laboratory at the University of Kiel, in Germany, decided to establish whether the rancher's recovery was due to some mind-over-MS miracle, or to some mystery ingredient in ruta leaves.

From leaf extracts of ruta and related plants, they purified a range of compounds, including khellinone -- a pigment-precursor molecule with weak but unusually selective activity as a potassium-channel blocker.

They discovered that khellinone blockades the Kv1.1 and Kv1.2 potassium channels, expressed by neurons. The two channels derive from alternative splicings of the Kv1 gene, and the latter had been identified as a key modulator of inter-neuronal signalling.

Normally, neuronal Kv1.2 potassium channels are silent beneath the neuron's shroud of myelin, extruded by neighbourly oligodendrocytes. One hypothesis is that demyelination exposes the channels, disrupting normal signalling. If so, a therapy to block these channels could restore normal neuronal signalling and ease the debilitating symptoms of MS.

One of Haensel's PhD Students, Heike Wulff, made an intriguing discovery: two khellinone molecules can react to form a dimer -- a double-header molecule that is a very potent blocker of a third form of the Kv1 potassium channel, Kv1.3.

The Kv1.3 channel is expressed, not in neurons, but in T-cells, particularly autoreactive T-cells, the agents provocateurs of autoimmune disorders. High expression levels make Kv1.3 an ideal target for drugs to treat MS and other autoimmune disorders like rheumatoid arthritis and scleroderma.

In the late 1990s, Dr Jonathan Baell, a medicinal chemist working at the now-defunct Biomolecular Research Institute in Parkville, began a research collaboration with Dr Wulff, now a postdoctoral researcher with electrophysiologist and potassium channel expert Prof George Chandy at the University of California, Irvine.

At the time, Baell's BRI colleague Dr Ray Norton was experimenting with sea anemone toxins that are potent blockers of Kv1.3 channels, but which aren't selective enough for a human therapeutic.

Wulff knew of Norton's work, and contacted him seeking a collaborator to modify khellinone as a potential drug for MS.

The native molecule is desirably small, but an unpromising human therapeutic because of its weak biological activity. Dimeric khellinone is far more potent, but similarly unpromising because of its hydrophobicity, high melting point, and its tendency to crystallise spontaneously.

Baell, who moved to the Walter & Eliza Hall Institute after the BRI was disbanded, worked with Wulff to synthesise and test analogues of khellinone. They were able to improve the solubility of the khellinone dimer, but at the cost of the compound's all-important selectivity for the Kv1.3 channel.

So Baell went back to scratch, synthesising analogues of the khellinone monomer. He obtained an immediate, dramatic improvement in selectivity and activity.

The best monomer analogue now selectively blockaded Kv1.3 channels at a 280 nanomolar concentration, compared to 70,000 nanomolar for native khellinone. Similar in potency to the highly active dimer, but a much smaller molecule, it looked to have far greater therapeutic potential.

All T-cells express the Kv1.3 potassium channel, but Chandy's research group at UC Irvine showed that autoreactive T-cells are especially sensitive to blockading because they are lack an accessory channel, KCa3.1, that can substitute for the Kv1.3 channel.

Baell and Wulff now had a candidate drug that was smaller, very potent, and highly selective for the Kv1.3 channel.

This year Chandy's team showed that myelin-reactive T-cells from the brains of MS patients express Kv1.3 channels at a very high level and that blocking the channels prevents them from activating and attacking myelin.

"If you have a Kv1.3 blocker that selectively inhibits autoreactive T-cells, it's big news," Baell said. "Kv1.3 is a relatively unexplored clinical target for MS and other autoimmune disorders, and has not been clinically validated.

"They [Chandy's team] have the lock, and we now have a molecular blu-tak to block it."

WEHI patented Baell's potent khellinone derivatives. Since then, he and Wulff, with help from postdoctoral chemist Dr Andrew Harvey, have developed compounds which are even more potent: they block Kv1.3 channels at concentrations of 80nM (= 0.08 micromolar).

WEHI licensed the IP, comprising three separate patents, to Iliad Pharmaceuticals, which was acquired by Adelaide biopharma Bionomics (ASX:BNO) this year. Bionomics now has the rights to develop a promising and novel drug candidate for multiple sclerosis.

Apart from humans, only miniature pigs and rats -- not mice -- are known to naturally express Kv1.3 in autoreactive T-cells. Bionomics is currently testing Baell's compounds in rats which exhibit a human-like autoimmune disorder to see if their symptoms abate.

This month Baell received the Royal Australian Chemical Institute's Biota Award for Medicinal Chemistry, for a paper describing his research, published in the Journal of Medicinal Chemistry.