As far as targeting kinases goes, inhibition is the only game in town. But that is not because there's no need for activators.
Kinases that no longer work like they should play a role in diseases including diabetes, cancer and Parkinson's disease. In the latter case, the kinase in question is PINK1. PINK1 is found in mitochondria, where its functioning is important to keep them healthy. Mutations in the PINK1 gene that reduce the enzyme's activity can lead to early onset Parkinson's disease.
Now, scientists have managed to identify an activator for PINK1 . The findings provide proof of principle that finding such kinase activators is possible. And the specific activator could prove useful in the treatment of Parkinson's.
"The drug is filling in for a natural substrate," Kevan Shokat told BioWorld Today. Shokat is at the University of California at San Francisco, and the senior author of the paper describing the work, which was published in the Aug. 15, 2013, issue of Cell.
Kinases, as a group, work by adding phosphates to their targets. They get those phosphates from adenosine triphosphate (ATP). But PINK1, it turned out, could also use KTP as the source of the phosphate group it attaches to BCL-xL, the anti-apoptotic protein that is its target.
In fact, PINK1 had an easier time with KTP than with ATP. In their experiments, Shokat and his team looked at two forms of PINK1.
One of them was the wild-type form; the other had a mutation that prevents it from binding ATP.
In cell culture, the team found that the mutant PINK1 was able to bind KTP and use it to phosphorylate BCL-xL. The mutant enzyme worked at near-normal levels when it was able to use KTP. The wild-type enzyme, too, used KTP when it was available – even when ATP, which it would normally use, was also around.
KTP itself does not cross the blood-brain barrier. But its precursor molecule kinetin does, and has been tested in clinical trials for the treatment of another disease, the splicing disorder familial dysautonomia.
Even in the large majority of patients whose Parkinson's disease is not due to PINK1 mutations, increasing the enzyme's activity might prove useful. Other studies have shown that revving up PINK1 beyond its natural activity levels in the cell protected neurons from cell death in response to toxins.
According to a UCSF press release, Shokat and co-author Nicholas Hertz "are inventors on a patent application related to kinetin and PINK1. UCSF has licensed the patent application to Mitokinin LLC, and Hertz and Shokat are co-founders and members of the company."
Shokat said that from his point of view, what makes the paper interesting is that "this comes up with a creative chemical solution to a genetic problem. . . . There are not very many druggable targets in Parkinson's disease that came out of the human genetics," he said, because those genetics have by and large identified proteins that are not working and would need an activator.
Activators have been hard to develop, not just for kinases but for other classes of drug targets as well. There are exceptions. Anti-anxiety drugs work by increasing the activity of GABA receptors, and thiazolidinediones, also which also go by the more pronounceable term glitazones, activate a nuclear hormone receptor known as peroxisome proliferator-activated receptors (PPAR) gamma. Finally, indirect activation can be achieved by inhibiting an inhibitor of the enzyme that is not working right. But by and large, Shokat said, an enzyme that is not working because it is mutated is "normally a showstopper," beyond the reach of what is considered druggable.
KTP will not find widespread use as a better form of ATP. It is too big to fit into the ATP-binding pocket of most kinases. And Shokat said that modifying medicinal chemistry via the typical methods would be a "pretty risky" strategy.
But as for the principle possibility of finding such activators, he added, "this proves that it's possible to do it."