A new study published in the Journal of Biological Chemistry revealed novel potential inhibitors of specific proteins involved in the pathogenesis of cancer and autoimmune disorders, like multiple sclerosis. The study is entitled “Dual Targeting of the Chemokine Receptors CXCR4 and ACKR3 with Novel Engineered Chemokines,” and was developed by an international research team with scientists from the University of Adelaide in Australia and the University of California, San Diego, in the United States.
“Cancer treatment is at the stage where the aim is to get more specific with treating different cancers so there are fewer side effects of chemotherapy,” explained the study’s co-author Professor Shaun McColl, Director of the Centre for Molecular Pathology at the University of Adelaide, in a news release. “Scientists working in this area are searching for precise molecular targets to inhibit or at least control disease like cancer and multiple sclerosis without harm to other parts of the body.”
CXCR4 and ACKR3 are cell membrane proteins that act as receptors of chemokines (signaling proteins), namely of the chemokine CXCL12. Together, these receptors regulate cell migration, a feature important for the spread of cancer cells to other parts of the body (metastasis) and also in the progression of autoimmune diseases. In fact, deregulation of CXCR4 and ACKR3 has been reported in several diseases.
Researchers have now engineered a new potent, high-affinity human CXCL12-based modulators of CXCR4 and ACKR3, which are able to strongly inhibit the activity of these receptors.
“Scientists around the world are looking for ways of blocking the CXCR4 and ACKR3 receptors as a means of preventing or at least slowing down the cell migration that underlies the progression of these diseases,” noted Professor McColl. “We hope these new molecules will be the basis for the design of new drugs that will interfere with cancer metastasis and inhibit multiple sclerosis.”
One of the modulator variants developed, LGGG-CXCL12, was found to have the highest affinity for CXCR4, and to be effective when tested in a mouse model of multiple sclerosis, potentially inhibiting the disease.
“The next stage of this research will be to use molecular modelling to work out exactly where these molecules are binding to the receptors and how they are disrupting their function so they can be further modified for even greater specificity,” said Professor McColl.
The team believes that the findings open new avenues for the development of novel therapies for cancer, multiple sclerosis, and other autoimmune disorders.