AMP-activated protein kinase, now that’s an enzyme for you. It sits at the center of a cell’s metabolic switchboard, and if you’re talking about anything to do with the response to levels of fuel like glucose or fatty acids and determination of their downstream fates, then AMPK is almost certainly crucial. Activating the enzyme sets off (among other things) downstream effects that cause fatty acids to get oxidized in the cell, glucose to be taken up from the bloodstream, cholesterol synthesis to be inhibited, breakdown of lipid stores to slow down, inhibition of triglyceride synthesis, and increased sensitivity in insulin release. A great many of the beneficial cellular effects of exercise are thought to involve activated AMPK. All sorts of metabolic drugs have been thought to have effects on its activity (metformin in particular, although that story is definitely complex and far from well understood), and as you’d imagine from that activity profile, modulating it somehow is of very great interest in the metabolic disease area.
That’s not easy. The enzyme has three subunits, each of which comes in different variations, so there are twelve varieties of the enzyme that are distributed in different tissues in ways that are incompletely understood. There are mutations known in these subunits, and some of them rev up the enzyme constantly. The problem is, these gain-of-function mutations seem to be partly compensated for during development on the metabolism end, while also leading to cardiac hypertrophy. So the question of “what happens when you activate AMPK out of the blue with a drug” is still open – is that heart effect something that happens just during development, or would you get that, too? The whole “human knockout” idea for disease and target understanding is a powerful one, but (like all the others) it has its limitations. Sometimes the only way to find out what a certain type of drug will do is go find yourself one of those drugs.
That’s what this paper from Merck has done. It describes an interesting-looking small molecule, MK-8722, that activates all twelve varieties of AMPK. I like that isosorbide on the right-hand side – it’s a cheap polar building block, and I’ve stuck it onto all sorts of compound classes over the years, just because it doesn’t always seem to be very well represented in compound screening libraries. (Here’s an earlier generation compound from this project, lacking that group). It’s potent and selective, and has good cell penetration and good PK properties in general – an excellent tool compound to start answering questions with. In rodents, acute dosing shows strong glucose-lowering (which is what you’d expect) in both lean normal and diabetic animals. In fact, it showed these effects in every single metabolic-disorder rodent model they tried, which is pretty impressive. Checking skeletal muscle tissue showed the expected changes consistent with increased glucose uptake and fatty acid metabolism. Chronic dosing in the classic db/db mice showed effects that were just as good as the PPAR compound rosiglitazone, but without any of its weight-gain effects. The same effects were seen in a diabetic rhesus monkey study (a difficult and expensive one to run, I should add). These all took place without raising insulin levels, as well.
So far, so good! But long-term dosing also revealed. . .cardiac hypertrophy. Just as in the (known gain-of-function mutations. It showed up in both the rats and the monkeys, and when dosing of the compound was discontinued, the heart tissue gradually went back to normal. Cardiac function didn’t seem to be impaired, but still. . .this could be a show-stopper. The paper notes that it’s similar to the heart effects seen in elite athletes, which might well also be AMPK-driven, but it’s going to take some hard thinking to decide what the long-term effects of causing this pharmacologically might be. It’s going to be interesting to see what Merck and the other companies working in this area decide to do about this. Safety (particularly cardiovascular safety) is a huge concern in the diabetes field, since patients basically take these drugs for the rest of their lives and are already at increased risk. This looks to me like a hard sell, both for physicians and for the FDA, but we’ll see. . .