Using a ‘kiss of death’ to neutralize disease-causing proteins

Drawing neutralizing proteins to cancer-causing proteins may make undruggable targets more vulnerable to treatments.

Many disease-causing proteins are stubbornly resistant to drug treatments. They include Ras and Myc in cancer, as well as Huntingtin, the protein that drives the progressive neurological disease Huntington’s. Scientists at the University of Dundee believe they have found a way to turn these previously undruggable proteins into vulnerable targets for new treatments.

They call their method the “kiss of death,” and it revolves around modifying small molecules so they draw neutralizing proteins to the bad proteins, which then causes them to degrade, according to a press release.

"Crucially, we have also found that it is not enough for this [neutralizing] protein to sit close to the bad protein, it has to make direct contact with it, to 'kiss' it,” said Alessio Ciulli, a professor at the University of Dundee, in the release. “And not just a little peck, but a real 'Gone With The Wind' embrace. We call this a 'kiss of death,' as it is the key to ensure the degradation of the bad protein."

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The researchers discovered they can use proteolysis-targeting chimeric molecules, which bind to both the bad proteins and the neutralizing molecule. They proved out the concept by pairing a cancer-causing protein called BRD4 with a degrader called MZ1. The MZ1 folded into itself, creating a magnet of sorts that led to the destruction of BRD4, according to the release. Their research was published in the journal Nature Chemical Biology.

Inhibiting BRD4 has been shown to be a powerful way to suppress Myc, a protein that drives many forms of cancer. Myc is often called a “regulatory protein” because it controls asymmetric cell division, which then affects the ability of immune cells to attack cancer. Last year, scientists at St. Jude Children’s Research Hospital suggested ways to manipulate the immune response to cancer by tweaking the production of Myc.

BRD4 is part of a family known as bromodomain and extraterminal domain (BET) proteins, and several drugs that inhibit them are in clinical trials. Last fall, scientists at the Wistar Institute published research showing that the BET inhibitor JQ1 is active against epithelial ovarian cancer cells.

The University of Dundee team hopes their method for neutralizing disease-causing proteins will prove to be an advance over current drug approaches, which disable those bad actors but don’t destroy them. "We now understand better how to turn inhibitors into degraders,” Ciulli said.