A promising protein degrader trashed a key oncogenic protein

Targeting oncogenic transcription factors like MYC is challenging, but researchers found a way to target its regulator, WDR5, for degradation, exemplifying the capacity of protein degraders to target the “undruggable.”

Jun 02, 2021
Natalya Ortolano, PhD
A promising protein degrader trashed a key oncogenic protein

Drugs often inhibit enzymatic activity, but it’s hard to pharmaceutically target scaffolding proteins. A tumor biologist and a medicinal chemist combined their expertise to develop a work-around: a new molecule that destroys a cancer-causing scaffolding protein in cancer cells. They hope it will work as well in mice as it does in a dish.

Elmar Wolf, a self-described molecular tumor biologist from the University of Wurzburg, and Stefan Knapp, a medicinal chemist from Goethe University, Frankfurt in Germany  — co-corresponding authors of a new study published last week in the Journal of Medicinal Chemistry — thought that inhibiting the function of an oncogenic scaffolding protein wasn’t enough. So, they developed protein degraders, an emerging therapeutic tool, to completely remove the protein from the cells. 

Protein degraders work just as their name implies; they target specific proteins for ubiquitin-mediated degradation by the cell’s “trash can,” the proteasome. Protein degraders are new to the scene  the first clinical trial testing the efficacy of an anticancer protein degrader started just last year. But they hold promise to completely remove a protein’s function rather than simply limiting it.

“Proteins or enzymes could have additional scaffolding functions, and if you just inhibit their enzymatic function, that enzymatic function is dead, but the protein is still there. It could still do something,” said Wolf.

Wolf credits his new drug development savvy to Knapp.

“I had no clue about drugs,” Wolf said. “Only together could we do these things. We profited a lot from the expertise of each other.” 

The two synthesized anticancer protein degraders to target the histone regulatory protein WDR5, which regulates the expression of several oncogenic proteins in cancer, including the transcription factor MYC, which is commonly overexpressed in cancer. Drugs inhibiting WDR5 function are also in development, but these only target specific protein-protein interactions leaving WDR5 free to continue performing its other duties. 

“By just inhibiting one interface of WDR5 with another protein, you would not necessarily inhibit all of its oncogenic functions. And that brought us to the idea of degrading it. We wanted to get rid of it completely and not only inhibit certain interfaces,” said Wolf.

Wolf and Knapp used two previously developed inhibitors to create molecules known as proteolysis targeting chimeras (PROTACs). These molecules look like a dumbbell with one end containing a WDR5 inhibiting ligand linked to a domain that recruits protein degradation machinery.

The most effective PROTAC depleted the levels of WDR5 by about 60%, resulting in a significant decrease in cancer cell proliferation when compared to cells treated with only the WDR5 inhibiting ligand.

Wolf is excited by how well the new molecule depletes WDR5 in cancer cells in vitro, but he knows that there is more work to be done. He wants to fine-tune these molecules to increase degradation of WDR5 in cells, which requires further functional analysis of how these ligands structurally interact with WDR5 and why they seem to only target a sub-population of the protein.

Once he perfects these new protein degraders, he wants to start preclinical testing. 

“We can kill cancer cells with our [molecule] much more efficiently than with [previously developed] ligands...but we don’t know how a normal body would react upon depletion of WDR5,” he emphasized. “This is definitely something we would have to address.”

Wolf believes that protein degraders are the wave of the future, and he hopes that his drug can ride that wave.

“You can drug so many more proteins that you could never drug with inhibitors because there was nothing to inhibit...because there is no enzymatic function,” he said. “It just opens up the universe of druggable proteins.”


Bikash et al. Design, synthesis, and evaluation of WD-Repeat-Containing Protein 5 (WDR5) degraders. Journal of Medicinal Chemistry. (2021).

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