New Screening Technique Accelerates Cancer Drug Discovery

Researchers in the United Kingdom have developed a screening technique that can accelerate the discovery of cancer-fighting drugs by identifying molecules that can prevent dangerous proteins from interacting with cells’ DNA.

Drug discovery is slow, costly and complex. Often, researchers are on a quest to find pharmaceutical molecules that can bind to sites on disease-causing proteins. But binding to a target site is not enough. A therapeutic molecule must also be able to shut down the dangerous protein, and most importantly, do so in a live cell without too many side effects.

The new method, dubbed Transcription Block Survival (TBS), addresses a major shortcoming of other screening methods: identifying functionally active inhibitors. “A big challenge is finding ways to ensure functional loss of detrimental protein activity within the demanding environment of a cell,” says principal investigator Professor Jody Mason, who is based in University of Bath’s Department of Biology & Biochemistry.  “Using the TBS approach, at the very first pass we’re able to eliminate molecules that stick to the cell target but that ultimately fail to knock out the function of the disease-causing protein. By removing molecules from the screening process that ultimately have little or no therapeutic value, we’ll save a lot of time and money.”

Mason and coauthors applied TPS to find peptides that permanently suppress the activity of a protein called Activator Protein-1 (AP-1). AP-1 is present naturally in the body and is important in switching on genes involved in many cellular processes, but when out of control, it promotes the growth of cancerous cells first by binding to gene promotors in specific sections of a cell’s DNA, and then by hijacking the expression of key genes by permanently switching them on.

“Using the TBS screening platform, researchers can find peptides that bind AP-1 in such a way as to guarantee that it cannot overstimulate cancer-related genes,” says coauthor Dr. Andrew Brennan, also from Bath’s Department of Biology & Biochemistry. “These peptides can both block AP-1 from binding to DNA or kick AP-1 off genes it has already paired with, allowing them to turn off the cancerous signal in vulnerable cells.”

Established drug-screening techniques already allow scientists to identify cancer-beating peptides by their ability to bind AP-1. But a major strength and distinguishing feature of TPS is that it allows scientists to identify peptides that can recognize/bind to AP-1 both before it has bound to DNA and when it is in a DNA-bound state—ultimately freeing AP-1 from DNA and shutting down its function altogether.

“This ability to distinguish between AP-1 binders and those that are capable of shutting down AP-1 function is unique to this technique and addresses a problem that until now has hampered the search for 'functionally active' inhibitors,” says Mason adds.

TBS has wider implications, as the proteins involved in cancer also play a central role in many other diseases, including osteoporosis and inflammatory diseases like rheumatoid arthritis and psoriasis.

Another distinguishing feature of TBS is that the screening technique happens within live cells and without modifying either the protein target or the peptide library with tags that may alter function, a common issue with other techniques. Most established screening methods involve testing peptides in vitro, meaning target binding is the only factor under consideration. This can result in false positives.

“What you often find when screening is done using traditional methods is that a peptide appears to work on an isolated protein but doesn’t have the same effect when it’s used within a cellular context, and it certainly does not guarantee the functional loss of the protein,” says Professor Mason.

The findings were published in the journal JACS Au.