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KL-50: A Novel Therapeutic Agent Targeting MGMT-Deficient Glioblastoma.
Neuro Oncol
January 2025
Duke University Medical Center, Duke University, Durham, NC, USA.
The novel DNA cross-linking agent KL-50 is active against patient-derived models of new and recurrent post-temozolomide mismatch repair-deficient glioblastoma.
Neuro Oncol
December 2024
Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago IL.
Article Synopsis
- Acquired resistance to temozolomide (TMZ) in glioblastoma patients, particularly those with DNA mismatch repair deficiencies, limits treatment effectiveness, prompting research into the new drug KL-50, which targets cancer cells in an MMR-independent manner.
- In studies, KL-50 significantly improved the median survival of mice with both naive and post-TMZ glioblastoma xenografts, showcasing its potential as a superior treatment option.
- Results indicate KL-50 may be particularly effective in MGMT and MMR-deficient tumors, offering hope for better management of recurrent glioblastoma after initial TMZ therapy.
Mechanism of Action of KL-50, a Candidate Imidazotetrazine for the Treatment of Drug-Resistant Brain Cancers.
J Am Chem Soc
July 2024
Department of Chemistry, Yale University, New Haven, Connecticut 06520, United States.
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 that the novel N3-(2-fluoroethyl)imidazotetrazine "KL-50" is a selective toxin toward tumors that lack the DNA repair protein O-methylguanine-DNA-methyltransferase (MGMT), which reverses the formation of O-alkylguanine lesions.
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