Published: 21-01-2020 11:00 | Updated: 21-01-2020 14:13

New opportunity for cancer drug development

After years of research on cell surface receptors called Frizzleds, researchers at Karolinska Institutet provide the proof-of-principle that these receptors are druggable by small molecules. The results, which are published in the scientific journal Nature Communications, open for new strategies to treat different types of cancer.

For more than 20 years Frizzleds (FZDs) have been proposed as suitable therapeutic targets for the treatment of diverse forms of cancer and several other disorders, such as fibrosis and cardiovascular disorders. They belong to the family of G protein-coupled receptors, which are involved in the progress of many diseases and are very common targets for drugs.

Large efforts have been undertaken to attack FZDs using therapeutic antibodies and other biopharmaceuticals. It has not previously been possible to design small molecules that would target FZDs pharmacologically. The Schulte laboratory at the Department of Physiology and Pharmacology, Karolinska Institutet, has now repurposed an existing small-molecule drug targeting a related receptor and shown that it can bind to and activate FZDs.

May lead to new cancer treatments

Gunnar Schulte, professor at the Department of Physiology and Pharmacology
Gunnar Schulte. Photo: Stefan Zimmerman

“Our study provides proof-of-principle that it is possible to target FZDs with small molecules,” says Professor Gunnar Schulte, who led the study. “This is a breakthrough laying the basis for development of novel and improved compounds that target FZDs for the treatment of different types of cancer.”

Key to the discovery was on the one hand a basic understanding of FZDs as pharmacological receptors and on the other hand a technical advance in drug screening.

First small molecule that activates Frizzleds

“However, the most important driving force was a clever, translational idea by postdoctoral fellow Pawel Kozielewicz in my lab, who identified the first small molecule that activates a Frizzled receptor,” says Gunnar Schulte. “Furthermore, computer simulations performed by postdoctoral fellow Ainoleena Turku allowed validation of laboratory experiments presenting deep structural insight into receptor-drug interactions.”

The computer simulation shows the interaction between the Frizzled receptor FZD6 (white cartoon) and the drug molecule SAG1.3 (violet spheres). SAG1.3 acts as a so-called partial agonist.

The study was performed in collaboration with colleagues in Germany and Japan. It was financed by several funding bodies, including Karolinska Institutet, the Swedish Research Council, the Swedish Cancer Society, the Novo Nordisk Foundation, Marie Skłodowska‑Curie Actions (FP7), the Wenner-Gren Foundations, and the Olle Engkvist Byggmästare Foundation and relied on access to the Swedish National Infrastructure for Computing. The authors declare no conflict of interest.


“Structural insight into small molecule action on Frizzleds”. Paweł Kozielewicz, Ainoleena Turku, Carl-Fredrik Bowin, Julian Petersen, Jana Valnohova, Maria Consuelo Alonso Cañizal, Yuki Ono, Asuka Inoue, Carsten Hoffmann, Gunnar Schulte. Nature Communications, online 21 January 2020, doi: 10.1038/s41467-019-14149-3.