Researchers have long dreamed of being able to manipulate Frizzled receptors, which are involved in the development of embryos and cancer. Now researchers have finally figured out how to target Frizzleds with small molecules.
After years of research, Swedish researchers have finally succeeded in demonstrating that small molecules can be used to manipulate receptors of the Frizzled family.
This paves the way for developing entirely new types of anticancer therapies targeting these receptors that can potentially be used to combat many types of cancer, including cancer of the lung, colon and pancreas.
“Researchers previously tried to influence Frizzleds with antibodies that bind to conserved extracellular domains on the receptors. In my opinion, however, this is not the right approach, because this does not selectively disable specific receptors. Examining whether we can use small molecules as targeted medicine is therefore more interesting. We have now shown that this is possible,” explains Gunnar Schulte, Professor, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
The study has been published in Nature Communications.
The Frizzled family includes 10 receptors
Frizzleds comprise a family of 10 receptors, all of which activate a network of signalling pathways that are important for the well-being of the whole body.
For example, in embryonic development, Frizzleds ensure the body’s symmetry – that is, that the head and tail develop in the right direction.
Frizzleds also ensure that the cells on the inside of the intestinal wall are replaced at the high tempo required in an environment such as the intestines.
No wonder things also go horribly wrong when these important signalling pathways start to go haywire.
If mutations occur in Frizzleds, they can become overactivated on their own or when stimulated with a ligand, and this can lead to excessively rapid cell division – a hallmark of the development of cancer.
Mutations can also occur in accessory proteins or regulatory regions of the DNA resulting in high levels of receptor or ligands with a similar outcome.
“Thus, inhibition of Frizzleds is an interesting therapeutic strategy. However, cell division in stem cell niches such as the inside of the intestinal cells should not be affected. It is therefore important to develop compounds that attack the individual Frizzled subtypes very precisely without affecting the others, which are crucial to maintain physiological function,” explains Gunnar Schulte.
Molecule activates Frizzled receptors
In the recent study, researchers from Karolinska Institutet investigated whether a small signalling molecule known to activate Smoothened signalling may also act as a ligand on Frizzleds.
More precisely, the researchers investigated whether the Smoothened agonist SAG1.3 can also bind to and activate Frizzled 6.
Using powerful computer-based modelling, molecular dynamic simulations, and pharmacological experiments, the researchers showed that SAG1.3 bind Frizzled 6 (FZD6) and acts as a weak, partial agonist.
“SAG1.3 can create structural changes in Frizzled 6, which increases the activity of the receptor. This is the first proof of concept that small molecules can be used to target the Frizzleds,” says Gunnar Schulte.
Different receptors lead to different types of cancer
Now that researchers know how a small molecule can bind to Frizzled 6, they can leverage this knowledge to design other small molecules that have a similar binding mechanism.
These other molecules may then be either antagonists or agonists, which either inhibit or enhance the effect of a signalling pathway, depending on the purpose.
The molecules can also be adjusted to target individual Frizzled receptors, and this may be relevant in combating various types of cancer. For example, Frizzled 5 is often involved in the development of pancreatic cancer, whereas Frizzled 6 and Frizzled 7 are often involved in intestinal cancer.
“It is hard to say where this will have the greatest impact. Some types of cancer are characterized by mutations being very rare, while other mutations found downstream of Frizzled are found in 85% of all cases of colon cancer. The mutations that are common and characterized by either an upregulation of WNTs, Frizzled activity, or Frizzled expression will, however, be interesting if they can be targeted with an antagonist or an inverse agonist,” says Gunnar Schulte.
Method may identify potential medicines
The part of the new study related to identifying SAG1.3 as a Frizzled agonist is also interesting.
In refining methods of analysis, the researchers have found assays suitable to identify drugs that act through Frizzleds.
Using these assays, the researchers found that other Smoothened-targeting molecules can also interact with Frizzleds, including the Smoothened inverse agonist cyclopamine, which gives lambs one eye if the pregnant ewe eats plants containing cyclopamine.
“We believe that we can use this assay to find and develop new molecules that can be very selective towards different types of Frizzled receptors and can therefore be used therapeutically in various diseases, especially cancer,” explains Gunnar Schulte.
“Structural insight into small molecule action on Frizzleds” has been published in Nature Communications. In 2017 and 2019, the Novo Nordisk Foundation awarded grants to Gunnar Schulte for the projects “WNT/Frizzled communication as a druggable endocrine signalling system” and “Drugging Frizzleds with Small Molecules – It Is Actually Possible!”, respectively.