Jiyoon Park

A team of Yale researchers published two papers detailing a new way to treat disease through the human body’s natural protein-degradation pathways. The papers were published together in the journal Cell Chemical Biology on Nov. 9.

Molecular, cellular and developmental biology professor Craig Crews and his team of undergraduates, graduate students, postdoctoral researchers and professors have focused on exploring this kind of technology, called PROTAC, for the past 16 years. The two recently published papers are installments in a longer line of research.

“Inside a cell, there are proteins that go around destroying other proteins,” Crews said. “So what we’ve done is hijack that protein destruction machinery to now drag problem proteins to it for destruction.”

While previous research has applied this technology to treat breast cancer and prostate cancer, Crews’ research shows the potential of protein-degradation technology as a lung cancer treatment.

While the two papers published last week both dealt with the PROTAC system, they focused on different aspects of the technology. The first paper explained how the PROTAC technology can target mutant RTK proteins, which are cell-surface receptors that have been found to cause cancer in mutated forms. The second paper focused on PROTAC’s capacity to target other types of rogue proteins.

George Burslem, a co-author of one of the two papers, said PROTAC technology is uniquely effective in that it degrades problematic proteins rather than just inhibiting them.

PROTAC technology works when researchers bind small molecules selectively to rogue or mutated proteins they wish to target. This method co-opts normal protein degradation pathways, which will then destroy the proteins in question.

“We believe that targeted protein degradation could allow us to drug these previously thought to be undruggable proteins,” Burslem said.

Blake Smith ’16, a co-author of both papers, explained that proteins are considered “undruggable” when they bind only weakly to receptors and inhibitors, evading widely used destruction techniques. However, he added that PROTAC technology can still cause protein degradation even in cases of weak binding interactions.

Blake Smith said before the team’s research was conducted, it had been unclear whether PROTAC technology could act upon cytosolic targets, or proteins within a cell’s gooey inside. Smith, who began working in Crews’ lab in 2015 after taking a class with Crews, wrote his senior thesis based on his research in the lab.

“It’s very easy to do some experiments, but then to be involved in the writing and revision process, but you realize when you are part of that there’s a lot that goes into publication besides experimentation,” he said.

The team’s research has practical applications. Last week, Arvinas, a New Haven-based biopharmaceutical company Crews started in 2013, announced its first drug, which will use PROTAC technology to combat prostate tumors.

“My lab is focused on more understanding the basic concept — so the technology and more what’s possible from a theoretical point of view because that’s what’s appropriate in academia, but … [Arvinas is] doing more of the applied aspect,” Crews said.

Crews said he is optimistic about using PROTAC technology as one in an arsenal of weapons to treat cancer. He reiterated that unlike other cancer treatments, PROTAC combats the disease differently through degradation rather than inhibition.

“We’re not trying to turn off the protein,” he said. “We’re actually causing it to be eliminated and destroyed by the cell. So it’s a different strategy, a different approach that can hopefully address mechanisms of drug resistance.”

Carly Wanna | carly.wanna@yale.edu