Cancer Drugs Target FOSL1 and Molecular Glue Degrader Show Promise

Researchers at Virginia Commonwealth University reported a series of novel analogs of the compound T‑5224 that bind the FOSL1/JUN heterodimer, a driver of cancer stem cells in head and neck squamous cell carcinoma. One analog, called compound 3, reduced tumor cell proliferation ten‑fold compared with T‑5224 and inhibited migration and sphere formation in vitro. A PROTAC derived from T‑5224, VZPT059, achieved strong degradation of FOSL1 (DC50 ≈ 0.4 µM) and suppressed tumor growth in mouse xenograft models without causing weight loss.

Separately, scientists at Roswell Park Comprehensive Cancer Center described the investigational agent FL118 as a dual molecular‑glue degrader that targets the proteins DDX5 and UbE2T. By dismantling these upstream regulators, FL118 disrupted multiple survival pathways and showed high activity in preclinical models of pancreatic, colorectal, ovarian, prostate and pediatric sarcoma cancers. The drug remains experimental and has not received FDA approval.

These preclinical findings highlight new strategies—direct transcription‑factor inhibition and molecular‑glue degradation—to overcome resistance in aggressive cancers.