New opportunity for cancer drug development

January 21, 2020

After years of research on cell surface receptors called Frizzleds, researchers at Karolinska Institutet in Sweden 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.

"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.

"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."
-end-
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 Sk?odowska 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.

Publication: "Structural insight into small molecule action on Frizzleds". Pawe? 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.

Karolinska Institutet

Related Cancer Articles from Brightsurf:

New blood cancer treatment works by selectively interfering with cancer cell signalling
University of Alberta scientists have identified the mechanism of action behind a new type of precision cancer drug for blood cancers that is set for human trials, according to research published in Nature Communications.

UCI researchers uncover cancer cell vulnerabilities; may lead to better cancer therapies
A new University of California, Irvine-led study reveals a protein responsible for genetic changes resulting in a variety of cancers, may also be the key to more effective, targeted cancer therapy.

Breast cancer treatment costs highest among young women with metastic cancer
In a fight for their lives, young women, age 18-44, spend double the amount of older women to survive metastatic breast cancer, according to a large statewide study by the University of North Carolina at Chapel Hill.

Cancer mortality continues steady decline, driven by progress against lung cancer
The cancer death rate declined by 29% from 1991 to 2017, including a 2.2% drop from 2016 to 2017, the largest single-year drop in cancer mortality ever reported.

Stress in cervical cancer patients associated with higher risk of cancer-specific mortality
Psychological stress was associated with a higher risk of cancer-specific mortality in women diagnosed with cervical cancer.

Cancer-sniffing dogs 97% accurate in identifying lung cancer, according to study in JAOA
The next step will be to further fractionate the samples based on chemical and physical properties, presenting them back to the dogs until the specific biomarkers for each cancer are identified.

Moffitt Cancer Center researchers identify one way T cell function may fail in cancer
Moffitt Cancer Center researchers have discovered a mechanism by which one type of immune cell, CD8+ T cells, can become dysfunctional, impeding its ability to seek and kill cancer cells.

More cancer survivors, fewer cancer specialists point to challenge in meeting care needs
An aging population, a growing number of cancer survivors, and a projected shortage of cancer care providers will result in a challenge in delivering the care for cancer survivors in the United States if systemic changes are not made.

New cancer vaccine platform a potential tool for efficacious targeted cancer therapy
Researchers at the University of Helsinki have discovered a solution in the form of a cancer vaccine platform for improving the efficacy of oncolytic viruses used in cancer treatment.

American Cancer Society outlines blueprint for cancer control in the 21st century
The American Cancer Society is outlining its vision for cancer control in the decades ahead in a series of articles that forms the basis of a national cancer control plan.

Read More: Cancer News and Cancer Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.