Researchers can finally determine the efficacy of drugs in the brain

Breaking new ground 8. jun 2023 3 min Associate Professor of Neurobiology Michael Lin Written by Kristian Sjøgren

Researchers have developed a new method to determine the efficacy of drugs in the brain. A researcher says that the method may be very useful for developing drugs for Parkinson’s disease, dementia and brain cancer.

Developing drugs to combat diseases originating in the brain such as brain cancer or neurodegenerative diseases such as Parkinson’s disease or dementia is notoriously difficult. The problem is that the blood–brain barrier allows very few compounds to enter.

Investigating whether drugs even penetrate the barrier and have efficacy is very complicated and requires researchers to test potential drug candidates on mice, which then have to be killed to determine whether the drugs entered the brain. The researchers have to do this for every drug at any concentration every time, and this is very, very expensive.

However, there may be light at the end of the tunnel after researchers have developed a novel method to determine whether drugs have efficacy in the brain by using engineered bioluminescent enzymes that light up on drug activity. Using the method, researchers identified a drug for brain cancer that looks promising.

“Using the method, we found that a potential drug that is already being studied for cancer outside the brain also looks promising for brain cancer. This method is particularly suitable for screening drug candidates for efficacy in the brain and quickly focusing on those that look promising. It should be investigated further,” explains a researcher involved in the study, Michael Lin, Associate Professor of Neurobiology, Stanford University, Palo Alto, CA, USA.

The research has been published in ACS Central Science.

Kinases are promising drug targets in the brain

Kinases are promising as drug targets for various diseases related to the brain and central nervous system. Kinases often play a role in developing neurodegenerative diseases and brain cancer, and inhibiting the function of the kinases can probably also counteract the diseases.

Kinases are targets for various treatments for cancer outside the brain.

“Kinase inhibitors that can enter the brain are therefore a very important group of drugs for diseases of the central nervous system, but none have been approved for brain diseases. One reason is that testing whether kinase inhibitors have efficacy in the brain is expensive,” says Michael Lin.

Bioluminescent enzyme from a deep-sea shrimp

The method that Michael Lin has helped to develop can determine whether a kinase inhibitor has efficacy in the brain of a living animal without killing the animal and removing its brain. The method developed was based on a bioluminescent enzyme that originated from a deep-sea shrimp.

The enzyme is not initially assembled but only becomes so when it contacts a relevant kinase inhibitor. So if no kinase inhibitor is present in the brain, the enzyme is not assembled and does not light up. Conversely, if the relevant kinase inhibitor is present in the brain, the enzyme is assembled and begins to glow.

If the enzyme is used on mice and they are put in a black box, the enzyme produces enough light inside the mice’s brains that a camera can capture it.

The enzyme itself is introduced into the brain in an ingenious way. The researchers let a virus that contains the genetic code for the enzyme infect the brain so that the brain cells make the enzyme based on the genetic code.

“We can examine how much the enzyme lights up at baseline. Then we add the kinase inhibitor and see whether there is a difference. If the enzyme lights up more, it means that the kinase inhibitor has not only penetrated the brain but also inhibits the relevant kinases,” explains Michael Lin.

Developing drugs to combat brain cancer

Michael Lin and colleagues are interested in developing treatments for brain cancer, and the kinase ERK is a promising inhibitor.

To validate the newly developed method, the researchers examined a panel comprising five ERK inhibitors for efficacy in the brain.

The five ERK inhibitors had been developed as possible treatments for cancer outside the brain, but none had been tested to determine whether they could enter the brain.

Using the method, Michael Lin discovered which of the five ERK inhibitors had the greatest potential to penetrate the brain and are efficacious there and thus should be investigated in clinical trials involving people with brain tumours.

Michael Lin explains that ERK is just one of many potential kinase targets in the brain. The kinase PKB is also promising – both in Parkinson’s disease and brain cancer as well as in cancer outside the brain.

“We are focusing on developing the bioluminescent indicator method to examine the efficacy of many kinase inhibitors. Once we have developed the method to enable us to do this, we can investigate potential drugs for efficacy in the brain, and we also hope to be able to develop kinase-inhibiting drugs that work in the brain,” concludes Michael Lin.

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