The Protein Exterminators: PROTACs offer alternative to current drug treatments

Your house is infested with flies. The exterminators try their best to eliminate the problem, but they possess terribly bad eyesight. If you had the chance to give eyeglasses to the exterminators, wouldn’t you?

In some ways, cancer is similar to this insect quandary. A cancerous cell often becomes infested with a host of aberrant proteins. The cell’s exterminators, proteins called E3 ubiquitin ligases, then attempt to destroy these harmful variants, but they cannot properly identify the malevolent proteins. The unfortunate result: both beneficial and harmful proteins are destroyed. How can we give eyeglasses to the E3 ubiquitin ligases? Craig Crews, professor of chemistry at Yale University, has found a promising solution.

According to the National Cancer Institute, some 14 percent of men develop prostate cancer during their lifetime. This common cancer has been linked to overexpression and mutation of a protein called the androgen receptor (AR). Consequently, prostate cancer research focuses on reducing AR levels. However, current inhibitory drugs are not specific enough and may end up blocking the wrong protein.

Crews and his team have discovered an alternative. By using PROTACs (proteolysis targeting chimeras), they have been able to reduce AR expression levels by more than 90 percent.

“We’re hijacking E3 ubiquitin ligases to do our work,” Crews said. PROTACs are heterobifunctional molecules: one end binds to AR, the bad protein, and the other end binds to the E3 ligase, the exterminator. PROTACs use the cell’s own quality-control machinery to destroy the harmful protein.

“The exciting implication is we only need a small amount of the drug to clear out the entire rogue protein population,” Crews said.

To put his innovative research into action, Crews founded the pharmaceutical company Arvinas. Arvinas and the Crews Lab collaborate and research the exciting potential of PROTACs in treating cancer. PROTACs have been designed to target proteins associated with both colon and breast cancer.

In addition to researching PROTACs, Crews has unearthed other techniques to exterminate proteins. “What I wanted to do is take a protein [AR] and add a little ‘grease’ to the outside and engage the cell’s degradation mechanism,” Crews said. This grease technique is called hydrophobic tagging and is highly similar to PROTACs in that it engages the cell’s own degradation machine to remove the harmful protein.

Having been given eyeglasses to the E3 ligases, Crews is looking for new ways to optimize his technique. “My lab is still trying to fully explore what is possible with this technology,” he said. “It’s a fun place to be.”

Cover Image: Image courtesy of Yale University.