Creation of a new class of radiosensitizers for glioblastoma based on the mibefradil pharmacophore
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Sateja Paradkar1,3, James Herrington2, Adam Hendricson2, Piyasena Hewawasam2, Mark Plummer2, Denton Hoyer2, Ranjini K. Sundaram1, Yulia V. Surovtseva2,* and Ranjit S. Bindra1,3,*
1 Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06510-8034, USA
2 Yale Center for Molecular Discovery, Yale University, West Haven, CT 06516-0972, USA
3 Department of Pathology, Yale University School of Medicine, New Haven, CT 06510-8034, USA
* These authors jointly directed this work
|Yulia V. Surovtseva,||email:||[email protected]|
|Ranjit S. Bindra,||email:||[email protected]|
Keywords: glioblastoma; radiosensitizers; mibefradil; DNA repair; alternative non-homologous end joining
Received: December 18, 2020 Accepted: March 22, 2021 Published: April 27, 2021
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 in vivo pharmacokinetic studies of the top analogues with evidence of brain penetration. We also report a targeted siRNA-based screen which suggests a possible role for mTOR and Akt in DNA repair inhibition by this class of drugs. Taken together, these data reveal a new class of mibefradil-based DNA repair inhibitors which can be further advanced into pre-clinical testing and eventually clinical trials, as potential GBM radiosensitizers.
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