An estimated 20,000 new glioma cases are diagnosed in the United States every year, more than half of which are glioblastomas, the most common and aggressive brain tumor among adults. Few treatment options are available for these aggressive brain cancers, and the five-year survival rate is less than 5%.
A research team led by Yale Cancer Center members Seth Herzon, PhD, and Ranjit Bindra, MD, PhD, developed new molecules that exploit a specific DNA-repair defect in these brain cancers to achieve tumor-specific cell killing. The team analyzed the DNA damage repair protein methylguanine methyl transferase (MGMT) and its ability to restore DNA to its native state. In their upcoming presentation at the American Association for Cancer Research (AACR) Meeting in Orlando, Florida, they’ll highlight new data on the synthesis, discovery, and characterization of “KL-50,” an imidazotetrazine derivative that has shown to overcome acquired drug resistance, while maintaining high selectivity for MGMT–cells.
“The poster describes mechanism of action studies of KL-50, a novel lead for the treatment of drug-resistant brain cancers. The compound is highly efficacious and well-tolerated in PDX models of drug-resistant glioblastoma,” said Dr. Herzon, a professor of Chemistry at Yale.
The compound generates a specific form of DNA damage, known as an “interstrand cross-link,” which is highly toxic to cells. Dr. Herzon said their new findings bolster their mechanistic model and suggests KL-50 may be extensible to other tumor types harboring specific DNA repair defects. Modifi Bio, a New Haven biotech startup, focused on curing brain cancers, is taking the next step with their findings on KL-50. Dr. Herzon said, “The compounds are currently being developed by Modifi bio with the goal of entering the clinic in 2025.”
Eric Huseman, Kingson Lin, Susan Gueble, and Ranjini Sundaram co-authored the study published in Science. Anna Lo, Olga Fedorova, and Anna M. Pyle contributed to the new data to be presented at the AACR meeting.
The Yale Departments of Chemistry, Molecular, Cellular, and Developmental Biology, Therapeutic Radiology, Pharmacology, and Pathology in New Haven, Conn., collaborated on the study.
Learn more about the Herzon Lab.