There have been many headlines in recent days about a potential malaria cure. I'm not sure what set these off at this time, since the paper describing the work came out back in the spring, but it's certainly worth a look.
This all came out of the Medicines for Malaria Venture, a nonprofit group that has been working with various industrial and academic groups in many areas of malaria research. This is funded through a wide range of donors (corporations, foundations, international agencies), and work has taken place all over the world. In this case (PDF), things began with a collection of about 36,000 compounds (biased towards kinase inhibitor scaffolds) from BioFocus in the UK. These were screened (high-throughput phenotypic readout) at the Eskitis Institute in Australia, and a series of compounds was identified for structure-activity studies. This phase of the work was a three-way collaboration between a chemistry team at the University of Cape Town (led by Prof. Kelly Chibale), biology assay teams at the Swiss Tropical and Public Health Institute, and pharmacokinetics at the Center for Drug Candidate Optimization at Monash University in Australia.
An extensive SAR workup on the lead series identified some metabolically labile parts of the molecule over on that left-hand side pyridine. These could fortunately be changed without impairing the efficacy against the malaria parasites. The sulfonyl group seems to be required, as does the aminopyridine. These efforts led to the compound shown, MMV390048, which has good blood levels, passes in vitro safety tests, and is curative in a Plasmodium berghei mouse model at a single dose of 30 mg/kg. That's a very promising compound, from the looks of it, since that's better than the existing antimalarials can do. It's also active against drug-resistant strains, as well it might be (see below). Last month the MMV selected it for clinical development.
So how does this compound work? The medicinal chemists in the audience will have looked at that structure and said "kinase inhibitor", and that has to be where to put your money. That, in fact, appears to have been the entire motivation to screen the BioFocus collection. Kinase targets in Plasmodium have been getting attention for several years now; the parasite has a number of enzymes in this class, and they're different enough from human kinases to make attractive targets. (To that point, I have not been able to find results of this latest compound's profile when run against a panel of human kinases, although you'd think that this has surely been done by now). Importantly, none of the existing antimalarials work through such mechanisms, so the parasites have not had a chance to work up any resistance.
But resistance will come. It always does. The best hope for the kinase-based inhibitors is that they'll hit several malaria enzymes at once, which gives the organisms a bigger evolutionary barrier to jump over. The question is whether you can do that without hitting anything bad in the human kinome, but for the relatively short duration of acute malaria treatment, you should be able to get away with quite a bit. Throwing this compound and the existing antimalarials at the parasites simultaneously will really give them something to occupy themselves.
I'll follow the development of this compound with interest. It's just about to hit the really hard part of drug research - human beings in the clinic. This is where we have our wonderful 90% or so failure rates, although those figures are generally better for anti-infectives, as far as I can tell. Best of luck to everyone involved. I hope it works.