BUFFALO, N.Y., Aug 8: Scientists from Roswell Park Comprehensive Cancer Center report that the investigational anticancer agent FL118 functions as a dual molecular glue degrader that directly targets and degrades the proteins DDX5 and UbE2T, two emerging therapeutic targets linked to cancer survival mechanisms. Recently published in the Journal of Experimental & Clinical Cancer Research, the paper combines new experimental findings with a comprehensive review of relevant research.
The study suggests FL118’s broad anticancer activity may stem from its ability to dismantle DDX5 and UbE2T, upstream regulators that influence numerous survival pathways within tumors. The authors propose that this multitarget effect may underlie the compound’s high activity in preclinical models of pancreatic, colorectal, ovarian, prostate and pediatric sarcoma cancers.
“These two regulator proteins, DDX5 and UbE2T, are not simply single-pathway targets,” says 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, including DNA repair, epigenetic regulation, stemness, immune suppression and treatment resistance.”
New Entry in an Emerging Drug Class
The findings add to growing interest in molecular glue degraders, drugs designed to harness the cell’s natural protein-disposal machinery to eliminate disease-driving proteins that have historically been difficult to target.
The paper also offers a potential explanation for earlier findings showing FL118 can suppress multiple cancer-associated proteins, including survivin, Mcl-1, c-Myc, mutant KRAS and androgen receptor signaling. The authors point to data newly reported in the paper as they propose that these downstream effects may result from FL118’s degradation of DDX5 and UbE2T.
FL118 remains an investigational agent and has not been approved by the U.S. Food and Drug Administration for cancer treatment. The findings are based on preclinical research and a review of existing evidence.
The cross-functional study team included several Roswell Park research leaders, among them Dean Tang, MD, PhD, Distinguished Professor and George Decker Endowed Chair in Developmental Therapeutics; Joyce Ohm, PhD, Professor and John & Santa Palisano Endowed Chair of Cancer Genetics; Scott Abrams, PhD, Professor and Jacobs Family Endowed Chair in Immunology; and Karen McLean, MD, PhD, FACOG, the Dr. M. Steven Piver Endowed Professor of Gynecologic Oncology at Roswell Park.