A new compound interrupts the “conversation” between cancer cells to put the brakes on tumor growth.
While great strides have been achieved in cancer treatment, scientists are looking for the next generation of therapeutics.
Researchers have developed a synthetic molecule, the “protein domain mimetic” that targets the interaction between two proteins at the point where intracellular signaling converges resulting in up-regulation of genes that promote tumor progression.
As reported in the Proceedings of the National Academy of Sciences, the compound is specifically designed to interrupt the type of molecular conversation within the cell called cell signaling.
“There is an urgent need to accelerate the discovery of mechanism-based anticancer therapeutics,” says Swati Kushal, a postdoctoral scholar in the School of Pharmacy at the University of Southern California.
“Traditionally, transcription factors and their complexes have been extremely challenging targets for drug design, mostly because it has been inherently difficult to find synthetic molecules that bind to their shallow surfaces with high affinity and specificity.”
For the most part, efforts to design compounds that can inhibit human transcription factors have been largely unsuccessful. But this study reports a successful approach spanning from concept to in vivo studies.
“When we embarked on this study several years ago, we did not realize how incredibly complex this research would be,” notes Bogdan Olenyuk, an assistant professor at the School of Pharmacy.
“Our collaborative efforts led us to design a stabilized protein fold that must bind to its target transcription factor complex with high affinity, regulating the activity of a traditionally ‘untreatable’ protein embedded in a highly complex cellular signaling network, correlating the in vitro and in vivo data and, lastly, analyzing the overall effects the compound produces.”
Of particular note, the synthetic molecule that the paper describes—HBS 1—is based on a chemically stabilized protein that mimics the specific molecule on which it has been modeled and shows outstanding potential for tumor suppression.
No signs of toxicity
Creation of HBS 1 required a method for locking correct helical shapes in synthetic strings of amino acids, a method previously developed at New York University.
The studies proved that the new approach disrupted the cancer cell “conversation” and reached the correct target in the cell, resulting in a rapid blockade of tumor growth. Furthermore, the compounds did not show any signs of toxicity or negative impact in the test host.
“Despite the fact that targeted protein complex turned out to be very uncooperative and capricious in our biophysical experiments, the synthetic molecule HBS 1, much to our delight, behaved well and produced a rapid and sustained disruption of hypoxia-inducible signaling network in cells, which translated into a robust suppression of the rate of tumor growth in our mouse models,” Olenyuk says.
While the in vivo experiments were conducted using renal cancer cells, the principles of this design are applicable to many human conditions, including other cancers, cardiovascular diseases, and diabetic complications.
The general concept of the study, the interruption of the connection between genes as they conspire to promote cancer growth, is general and applicable to the protein cell to protein cell “conversations” implicated in a host of human diseases.
Next, researchers will initiate the translational aspects of the project. The compounds will be tested in advanced tumor models with the aim to ultimately take the compound into clinical trials.
The National Science Foundation and the National Institutes of Health funded the study.