New Analogs of Mibefradil Created as Radiosensitizers for Glioblastoma

Current standard treatment for patients with glioblastomas (GBMs)—the most common primary malignant tumor of the central nervous system (often occurring in the brain or spinal cord)—is surgery, radiation therapy, and chemotherapy. However, despite these potent treatments, poor overall prognosis glioblastoma still recurs in most patients within 1–2 years. Given GBM’s dismal rates of recurrence, researchers have been seeking new strategies to better control these tumors. 

Since locoregional failure is common in glioblastomas (even with high doses of radiation therapy) many researchers have been particularly interested in discovering new radiosensitizer drugs. A team from Yale University and Yale School of Medicine authored a new research paper, chosen as the cover of Oncotarget’s Volume 12, Issue 9, and entitled, “Creation of a new class of radiosensitizers for glioblastoma based on the mibefradil pharmacophore.”

The Study

Previously, the above researchers identified a calcium channel blocker (CCB), mibefradil, as a potential glioblastoma radiosensitizer. However, while mibefradil does selectively inhibit a key DNA repair pathway, its use in the researchers’ phase I clinical trial was hampered by dose-limiting toxicities and its FDA approval for hypertension was withdrawn. 

“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.”

In the current study, based on their previous findings, the researchers aimed to create, synthesize, and profile a series of 140 mibefradil analogs. Their goal was to develop superior mibefradil analogues, reduce their off-target effects, and improve potency. To achieve this, the team used structure activity relationship analysis and carried out calcium channel activity studies, EJ-DR 384-well plate assays, automated hERG inhibition patch clamp assays, cytochrome P450 inhibition assays, quantitative reverse transcription PCR (RT-qPCR), siRNA studies, statistical analyses, and more.

The researchers successfully reduced the known off-target liabilities of mibefradil in their analogs. They selected the top 12 analogs for further in vitro and in vivo studies. Pharmacokinetic parameters of these synthesized analogs were tested in vivo, and researchers verified that they indeed crossed the blood-brain barrier and accumulate in mouse brain tissue in quantities similar to that of mibefradil.

“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.”

Conclusion

The researchers found that the mibefradil analogue, YU252386, showed the greatest improvement in pharmacokinetic profile compared to mibefradil. 

“The synthesis and validation of the mibefradil analogue, YU252386, shows great promise towards the development of a potent and selective radiosensitizer for GBMs and beyond, and warrants further in vivo study in clinically relevant GBM models.”

This new class of radiosensitizers retain the DNA repair inhibition quality of mibefradil, but demonstrate reduced CCB activity and attenuated hERG and CYP450 enzyme inhibition. Additional testing may deem these analogs fit for clinical trials to improve radiosensitivity in the treatment of glioblastomas.

“These analogues could further be tested as radiosensitizers in in vivo models and eventually clinical trials for improving RT [radio therapy] efficacy in GBMs.”

Click here to read the full scientific study, published by Oncotarget.

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