These oncotarget data reveal a new class of mibefradil-based DNA repair inhibitors that can be further developed as potential GBM radiosensitizers in preclinical testing and ultimately clinical trials
Oncotarget released “Creation of a new class of radiosensitizers for glioblastomas based on the mibefradil pharmacophore”, Who reported that this group had previously identified a calcium channel blocker, mibefradil, as a potential GBM radiosensitizer. They discovered that mibefradil selectively inhibits an important DNA repair pathway, an alternative non-homologous end link.
They then initiated a Phase I clinical trial that showed promising initial efficacy for mibefradil. However, further development has been hampered by dose-limiting toxicities, including CCB-related cardiotoxicity, interactions between hERG channel and cytochrome P450 enzymes out of target.
Here, the authors show that mibefradil inhibits DNA repair regardless of its CCB activity, and report a number of mibefradil analogs that lack CCB activity and that have decreased hERG and CYP activity while being effective is retained as DNA repair inhibitors. They also report on targeted siRNA-based screening that suggests a possible role for mTOR and Akt in inhibiting DNA repair by this class of drugs.
Taken together, these oncotarget data reveal a new class of mibefradil-based DNA repair inhibitors that can be further developed as potential GBM radiosensitizers in preclinical testing and ultimately clinical trials.
These oncotarget data reveal a new class of mibefradil-based DNA repair inhibitors that can be further developed as potential GBM radiosensitizers in preclinical testing and ultimately clinical trials.
Dr. Yulia V. Surovtseva and Dr. Ranjit S. Bindra of Yale University said: “Glioblastoma (GBM) is the most common primary malignant tumor of the central nervous system (CNS).“
Cells use multiple DNA double-strand break repair pathways to repair radiation-induced DNA damage.
This pathway repairs only 0.5-1% of total DSBs, but serves as a critical backup pathway for both NHEJ and HR and for repairing complex DNA lesions caused by IR-induced damage.
The EJ-DR assay was used in a high throughput chemical screen for novel DNA repair inhibitors in which the T- and L-type calcium channel blocker, mibefradil, was identified as a selective inhibitor of Alt-NHEJ repair.
Based on these findings, the authors searched for a new class of radiosensitizers that retained the activity of mibefradil as a DNA repair inhibitor, but showed decreased inhibition of hERG and CYP450 enzymes.
Finally, through the degradation of DNA damage response proteins in the high-throughput imaging assay, we identified potential targets or regulators of mibefradil that phenocopy the selective inhibition of Alt-NHEJ versus HR.
The Surovtseva / Bindra research team concluded in their Oncotarget Research suggests that using DNA repair inhibitors as radiosensitizers in GBM could be a viable approach to provide a better response due to the range of DDR pathways activated in response to radiation-induced DNA damage.
In addition, the identification of selective inhibitors of Alt-NHEJ could also be tested in other settings where Alt-NHEJ activity is critical, such as HR-deficient tumors.
The synthesis and validation of the mibefradil analog YU252386 shows promise for the development of an effective and selective radiosensitizer for GBMs and beyond and warrants further in vivo studies in clinically relevant GBM models.
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Correspondence – Julia V. Surovtseva – [email protected] and Ranjit S. Bindra – [email protected]
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alternative non-homologous termination
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