2. Academic Validation
  3. Development of Selective and Soluble Mitochondrial Complex 1 Inhibitors Derived from Papaverine for Radiosensitization of Cancer

Development of Selective and Soluble Mitochondrial Complex 1 Inhibitors Derived from Papaverine for Radiosensitization of Cancer

  • J Med Chem. 2025 Nov 13;68(21):23140-23162. doi: 10.1021/acs.jmedchem.5c02014.
Ben J Haines 1,  McKenzie Kreamer 2,  Martin Benej 2 3,  Shabber Mohammed 1,  Haylee Bridge 1,  Esin Bayrali-Ulker 2,  Adel Fergatova 2,  Terence M Williams 4,  Zihai Li 5,  Ioanna Papandreou 2,  Nicholas C Denko 2 5,  Mark J Mitton-Fry 1
Affiliations

Affiliations

  • 1 Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, Ohio 43210, United States.
  • 2 Department of Radiation Oncology, The Ohio State University Comprehensive Cancer Center, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, Ohio 43210, United States.
  • 3 Department of Molecular Medicine and Therapeutics, The Ohio State University Comprehensive Cancer Center and College of Medicine, The Ohio State University Wexner Medical Center, Columbus, Ohio 43210, United States.
  • 4 Department of Radiation Oncology, City of Hope National Medical Center, Duarte, California 91010, United States.
  • 5 Pelotonia Institute for Immuno-Oncology, The Ohio State University Comprehensive Cancer Center, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, Ohio 43210, United States.
PMID: 41110127 DOI: 10.1021/acs.jmedchem.5c02014
Abstract

The efficacy of radiation therapy is limited by low oxygen tension within solid tumors. Papaverine and some derivatives were previously shown to inhibit mitochondrial complex 1 and decrease oxygen consumption, reversing hypoxia and radiosensitizing model tumors. Papaverine is typically used as a vasorelaxant due to its ability to inhibit phosphodiesterase 10A (PDE10A), which can lead to unwanted side effects when used clinically as a radiosensitizer. We have therefore generated additional derivatives which have improved mitochondrial complex 1 inhibition and reduced PDE10A inhibition. Two of these compounds were tested in vivo for radiosensitization of murine EO771 mammary gland tumors and found to be as effective as papaverine with an improved safety profile.

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