Creation of a new class of radiosensitizers for glioblastoma based on the mibefradil pharmacophore.
DNA repair
alternative non-homologous end joining
glioblastoma
mibefradil
radiosensitizers
Journal
Oncotarget
ISSN: 1949-2553
Titre abrégé: Oncotarget
Pays: United States
ID NLM: 101532965
Informations de publication
Date de publication:
27 Apr 2021
27 Apr 2021
Historique:
received:
18
12
2020
accepted:
22
03
2021
entrez:
6
5
2021
pubmed:
7
5
2021
medline:
7
5
2021
Statut:
epublish
Résumé
Glioblastoma (GBM) is the most common primary malignant tumor of the central nervous system with a dismal prognosis. Locoregional failure is common despite high doses of radiation therapy, which has prompted great interest in developing novel strategies to radiosensitize these cancers. Our group previously identified a calcium channel blocker (CCB), mibefradil, as a potential GBM radiosensitizer. We discovered that mibefradil selectively inhibits a key DNA repair pathway, alternative non-homologous end joining. We then initiated a phase I clinical trial that revealed promising initial efficacy of mibefradil, but further development was hampered by dose-limiting toxicities, including CCB-related cardiotoxicity, off-target hERG channel and cytochrome P450 enzymes (CYPs) interactions. Here, we show that mibefradil inhibits DNA repair independent of its CCB activity, and report a series of mibefradil analogues which lack CCB activity and demonstrate reduced hERG and CYP activity while retaining potency as DNA repair inhibitors. We present
Identifiants
pubmed: 33953843
doi: 10.18632/oncotarget.27933
pii: 27933
pmc: PMC8092340
doi:
Types de publication
Journal Article
Langues
eng
Pagination
891-906Subventions
Organisme : NCI NIH HHS
ID : P30 CA016359
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR001863
Pays : United States
Informations de copyright
Copyright: © 2021 Paradkar et al.
Déclaration de conflit d'intérêts
CONFLICTS OF INTEREST R.S.B. is a co-founder, consultant, an equity stockholder of Cybrexa Therapeutics; and a co-founder and equity stockholder of Athena Therapeutics. The Bindra lab has received sponsored research funds from both companies, but neither are related to the work that is presented here.
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