How Experimental Drug FL118 'Unsticks' Cancer's Survival Machinery

Roswell Park scientists report that the investigational agent FL118 works as a 'dual molecular glue degrader,' directly targeting and degrading two proteins — DDX5 and UbE2T — that anchor multiple cancer survival networks. Published in the Journal of Experimental & Clinical Cancer Research, the findings may explain the drug's broad activity against hard-to-treat cancers.

Key Takeaways

Roswell Park scientists report that the investigational agent FL118 works as a 'dual molecular glue degrader,' directly targeting and degrading two proteins — DDX5 and UbE2T — that anchor multiple cancer survival networks.
Published in the Journal of Experimental & Clinical Cancer Research, the findings may explain the drug's broad activity against hard-to-treat cancers.

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A drug still in the laboratory may work in a way that helps explain why it has shown such broad promise against difficult-to-treat cancers. Scientists at Roswell Park Comprehensive Cancer Center report that the investigational agent FL118 acts as a 'dual molecular glue degrader,' latching onto two proteins — DDX5 and UbE2T — and marking them for destruction by the cell's own disposal machinery.

The study, published in the Journal of Experimental & Clinical Cancer Research, combines new experimental data with a comprehensive review of the field. The two proteins sit high in the hierarchy of tumor survival: they influence DNA repair, epigenetic regulation, stemness, immune suppression and treatment resistance.

"These two regulator proteins are not simply single-pathway targets," said corresponding author Fengzhi Li, PhD, Associate Professor of Oncology in Roswell Park's Department of Pharmacology & Therapeutics. "They are linked to multiple cancer survival networks."

Molecular glue degraders are an emerging class of drugs that hijack the ubiquitin-proteasome system — the cell's garbage-disposal network — to eliminate disease-driving proteins that have traditionally been considered 'undruggable.' FL118's distinguishing feature, the authors propose, is that it degrades two such regulators at once.

The discovery may also tie together years of puzzling observations. FL118 had previously been shown to suppress a wide array of cancer-associated proteins, including survivin, Mcl-1, c-Myc, mutant KRAS and androgen receptor signaling. The Roswell Park team suggests those downstream effects may all flow from the initial dismantling of DDX5 and UbE2T.

The compound has shown high activity in preclinical models of pancreatic, colorectal, ovarian, prostate and pediatric sarcoma cancers. The authors caution that FL118 remains an investigational agent, is not approved by the FDA, and the new findings are based on preclinical research. Still, the paper adds momentum to a drug class that is attracting growing attention — and offers a molecular explanation for why a single compound might attack cancer on so many fronts at once.