Mechanism of Action of KL-50, a Candidate Imidazotetrazine for the Treatment of Drug-Resistant Brain Cancers

• Published in: Journal of the American Chemical Society Vol. 146; no. 27; pp. 18241 - 18252
• Main Authors: Huseman, Eric D., Lo, Anna, Fedorova, Olga, Elia, James L., Gueble, Susan E., Lin, Kingson, Sundaram, Ranjini K., Oh, Joonseok, Liu, Jinchan, Menges, Fabian, Rees, Matthew G., Ronan, Melissa M., Roth, Jennifer A., Batista, Victor S., Crawford, Jason M., Pyle, Anna M., Bindra, Ranjit S., Herzon, Seth B.
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 10.07.2024
• Subjects: alkylation; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; brain; Brain Neoplasms - drug therapy; Brain Neoplasms - pathology; Cell Line, Tumor; crosslinking; cytidine; DNA; DNA repair; DNA Repair - drug effects; drug resistance; Drug Resistance, Neoplasm - drug effects; fluorides; Humans; Imidazoles - chemistry; Imidazoles - pharmacology; Imidazoles - therapeutic use; mechanism of action; mutagens; O-Methylguanine-DNA Methyltransferase - antagonists & inhibitors; O-Methylguanine-DNA Methyltransferase - metabolism; toxicity; toxins

Aberrant DNA repair is a hallmark of cancer, and many tumors display reduced DNA repair capacities that sensitize them to genotoxins. Here, we demonstrate that the differential DNA repair capacities of healthy and transformed tissue may be exploited to obtain highly selective chemotherapies. We show...