At a glance
Researchers have developed a method to quickly scan thousands of molecules to find molecular glue degraders that eliminate proteins driving cancer and other diseases.
The method could help scientists find ways to destroy proteins previously considered impossible to target with conventional medicines.
The platform identified the first molecular glue degrader activated only in cells with certain metabolic triggers, like those often found in cancer.
Harvard Medical School investigators at Dana-Farber Cancer Institute have developed a new laboratory method for systematically discovering molecular glue degraders — compounds that harness cells’ own waste-disposal machinery to destroy disease-causing proteins, including proteins that have been difficult to target with traditional drugs.
The new platform, reported Aug. 5 in Nature, could dramatically expand the search for molecular glue-based drugs, including protein degraders. Already, it has revealed a new way that molecular glue degraders can work.
“This novel platform is an exciting scalable approach to the discovery of molecular glues that could help drive […] the treatment of cancer and other diseases,” said co-senior author Eric Fischer, HMS professor of biological chemistry and molecular pharmacology at Dana-Farber.
Reaching undruggable proteins
Conventional drugs generally work by fitting into pockets on a protein and blocking its activity. However, many disease-causing proteins — including some transcription factors that are involved in cancer — lack such pockets and thus have largely been considered undruggable.
Protein degraders, which dispose of unwanted proteins from inside a cell using the cell’s built-in recycling system, offer a way to eliminate disease-causing proteins that conventional drugs have struggled to reach.
A molecular glue degrader is a type of protein degrader that works by binding to an enzyme called an E3 ligase and directing it to tag a disease-related protein for disposal.
Co-senior author Benjamin Ebert, the HMS Richard and Susan Smith Professor of Medicine at Dana-Farber and CEO of Dana-Farber, found in 2013 that the multiple myeloma drug lenalidomide works as a molecular glue degrader, prompting an E3 ligase to destroy specific transcription factors thought to be undruggable. The finding opened a new way of thinking about the treatment of cancer.
Since then, several protein degraders have entered clinical testing. However, these degraders only leverage a small handful of the 600 E3 ligases in the human genome, limiting the proteins that can be targeted for destruction in this way.
“There is an incredible range of opportunity for discovering new molecular glue degraders,” said Ebert.
A broader search
The new method is designed to cast a much wider net in the search for such degraders.
Unlike previous methods, it doesn’t require researchers to decide in advance which protein they want to destroy. Instead, it uses a broad screening technique to reveal previously unknown combinations of a compound, an E3 ligase, and a target protein.
One of those combinations led to a surprising discovery.
Spearheaded by co-first author Franziska Wachter, HMS instructor in pediatrics at Dana-Farber, the team identified the first molecular glue degrader that is activated by a metabolic process. They found that a compound called M12 can direct an understudied E3 ligase called DCAF11 to tag a protein called DDX18 for degradation — but only when M12 is altered by a metabolic process called glutathionylation. M12 would only act as a molecular glue inside cells with elevated levels of metabolites related to oxidative stress, something that is more common in cancer cells than normal cells.
“This was a huge surprise, and it is the first observation of a molecular glue that has been activated metabolically by glutathionylation,” said Wachter.
The finding raises the possibility of developing molecular glues whose activity depends on the metabolic environment of a cell, allowing for treatments that target diseased cells while minimizing effects in healthy tissue.
The researchers also found that the activated M12 could be adapted to degrade multiple other proteins, including cancer-related proteins such as SMARCA2, WEE1, and CDK7.
While more research is needed to identify the best molecular glue degraders to use as drug candidates, the work demonstrates the power of collaboration in the laboratory to drive clinical advances.
“This is a fabulous example of how powerful our combined expertise in cancer genomics, cell biology, structural biology, and protein biochemistry can be,” Ebert said.
Adapted from a Dana-Farber news release.
Authorship, funding, disclosures
Hojong Yoon is an additional co-first author. Other co-authors include Katharine A. Barrett, Cyrus Jin, Anna Rodríguez-Pöhnlein, Justine C. Rutter, Ryan J. Lumpkin, Rebecca J. Metivier, Katherine A. Donovan, Kheewoong Baek, Yongying Jiang, Minwoo Lee, Robert W. Kalis, Jianwei Che, and Yuan Xiong.
This work was supported by the National Institutes of Health (grants K00CA253754, K99CA298069, R00CA298069, K99GM154065, F30CA298680, R01CA262188, R01CA214608, P01CA066996, and R35CA253125), the Howard Hughes Medical Institute, and the Cancer Prevention and Research Institute of Texas (CPRIT) (award RR240076). Wachter is an American Society of Hematology Scholar. Barrett is a Meghan E. Raveis Fellow of the Damon Runyon Cancer Research Foundation (DRG-2514-24).
Ebert has received research funding from Novartis and Calico and consulting fees from AbbVie and is a member of the scientific advisory board and shareholder for Neomorph, Big Sur Bio, Skyhawk Therapeutics, and Exo Therapeutics. Fischer is a founder, scientific advisory board member, and equity holder of Civetta Therapeutics, Proximity Therapeutics, Neomorph (serving on the board of directors), Stelexis BioSciences, Anvia Therapeutics (serving on the board of directors), Nias Bio, and Vasetto Bio (serving on the board of directors); is an equity holder in Avilar Therapeutics, Ajax Therapeutics (serving as a member of the scientific advisory board), Photys Therapeutics (serving as a member of the scientific advisory board), HiddenSee Therapeutics, and Light Horse Therapeutics; and is a consultant to GSK, Novartis, and Deerfield Management. The Fischer Lab receives or has received research funding from Deerfield, Novartis, Ajax, Interline, Bayer, and Astellas. Donovan receives or has received consulting fees from Neomorph and Kronos Bio. Che is a co-founder for Matchpoint Therapeutics and M3Bioinformatics&Technology; is a consultant and equity holder for Matchpoint, Soltego, and Allorion Therapeutics; and has received sponsored research support from SpringWorks Therapeutics and Deerfield. The other authors declare no competing interests.
