Novel Compound Blocks Cancer Cells’ Protein Disposal System

September 25, 2020

Scientists in the lab of Loren Walensky, MD, PhD, have come up with a new twist on the emerging strategy of killing cancer cells by jamming their “garbage disposal” mechanism for getting rid of abnormal or unwanted proteins.

Dana-Farber researchers created a novel peptide molecule that binds to a key control point in what’s known as the ubiquitin-proteasome system (UPS). The UPS, a survival mechanism, enables cells to dispose of proteins which, if allowed to accumulate, cause toxic stress that kills cells.

In recent years, drug developers have begun exploiting this system with drugs such as bortezomib (Velcade) for multiple myeloma and mantle cell lymphoma. Bortezomib inhibits the proteasome, a structure in the UPS that eliminates proteins tagged for degradation: without an effective protein disposal system, the myeloma cells self-destruct.

Reporting in Nature Chemical Biology, Walensky and his colleagues, including Harvard MD-PhD student and first author Ann Cathcart, PhD, describe how they developed a compound that targets a different component of the UPS than bortezomib.

Loren Walensky, MD, PhD.

Designing a special molecule

The researchers designed a peptide molecule that blocks the first critical step of the UPS process where proteins are marked with chemical tags for disposal. Their compound, a stapled peptide with helical structure, fits into a groove in a key UPS protein called E1, blocking an interaction between E1 and another UPS enzyme, E2. The stapled peptide accomplishes this by mimicking a part of the structure of the E2 enzyme. The researchers say their findings indicate that the groove or pocket in the E1 enzyme is a potentially druggable site, and could serve as a blueprint for expanding the arsenal of cancer drugs that target the UPS.

“Cancer cells make many more proteins, including defective ones, to sustain their excessive growth compared to normal cells, so they rely on an efficient garbage disposal system,” explains Walensky. That is why blocking UPS system preferentially affects cancer cells more than normal cells — producing a “therapeutic window” in which a carefully calculated dose of a UPS-blocking drug can kill cancer cells but spare normal cells.

The UPS process begins with the activation of the ubiquitin protein by an enzyme called E1. Then the ubiquitin tag is sequentially transferred from E1 to a site on the E2 enzyme, which in turn works together with an E3 enzyme to ultimately tag and target the unwanted protein for degradation via the proteasome.

Drugs like bortezomib obstruct the UPS process at this final step, the proteasome, but scientists have also been interested in attacking earlier steps of the cascade. Here, the Walensky group has blocked the enzyme responsible for the very first step of the UPS – which would result in a toxic buildup of unwanted proteins.

To accomplish this with precision, Cathcart, Walensky, and their team of investigators created molecules that inhibit the transfer of ubiquitin from E1 to the diversity of E2 enzymes. The Walensky lab specializes in building peptides — the building blocks of proteins — which are chemically “stapled” to maintain their natural bioactive shape when interacting with target proteins. Importantly, the researchers exploited a mechanism by which E2 enzymes dock into the E1 enzyme to create synthetic stapled peptides that fit into the “groove” of the E1 enzyme, blocking the binding needed to transfer ubiquitin from E1 to E2. From this group of stapled peptides, they identified one that worked most efficiently.

“This stapled peptide could itself be developed as a therapeutic”, or it could serve as a blueprint for developing small molecule drugs based on the mechanism we identified for stapled peptide blockade of the UPS, says Walensky. “We believe this is an exciting new strategy for cancer therapy.”